Molekulare Medizin: Grundlagen, Pathomechanismen, Krankheitsbilder

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Author: Matthias W. Hentze | Andreas E. Kulozik | C. R. Bartram | Christian Hagemeyer

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TATA TFIID

TFIID TATA TFIIA TFIIB TFIID TFIIA

TFIIB

TATA POL II TFIIF

Mediator/ SRB

POL II

TFIID TFIIA

TFIIF

TFIIB

TATA TFIIE TFIIH

Mediator/ SRB

POL II

TFIID TFIIA

TFIIF

TFIIB

TATA

TFIIE TFIIH

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POL II

TFIID TATA

PP

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TFIIE TFIIH

VY

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U2AF GUC CAUUCA I I I I I I I I I C A G GU A A G U Exon 1

5´

AUGAU I I I I I UACUA

IAI

G I C

Py

CAGG Exon 2

Verzweigungspunkt + U5, U4/U6

G A C 1 on Ex

UACUA C II A G AU UGA

Py

UACUA C II A G AU UGA

Py

CAGG Exon 2

CAG

CAG G Exon 1 Exon 2

Assemblierung des Spleißosoms

Schritt 1 = Ausbildung der Lassostruktur = 1. Transesterifizierung

Schritt 2 = Zusammenspleißen des Exons, Freisetzung des Lariats = 2. Transesterifizierung

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[V

U o2/(.8/$50(',=,1,6&+( r+&+67 817(56&+,('/,&+( x(56$7=67@&.( '(6 %(75(5(1'(1 i(1/2&86 =8 (,1(5 ,1',9,'8(//(1 k1)250$7,21 =86$00(1*(6(7=7P g567 ',(6( 1(8 5(.20%,1,(57(1 fpcOu(48(1=(1 :(5'(1 '$11 75$16.5,%,(57 81' (17635(O &+(1' '(1 2%(1 %(6&+5,(%(1(1 r5,1=,3,(1 ,1 (,1 r527(,1 @%(56(7=7P o$1 817(56&+(,'(7 dO|(//(1N ',( $/6 $86',5(5(1=,(57( r/$60$=(//(1 k0081*/2%8O /,1( ,16 d/87 6(=(51,(5(1 J+8025$/( c%:(+5K 921 vOn5( c%:(+5 9(50,77(/1P k0O 081*/2%8/,1( Jk*K 6(7=(1 6,&+ (%(162 :,( vO|(//Ot(=(3725(1 JvetK $86 =:(, 9(5O 6&+,('(1(1 m(77(171=7N :(/&+(5 '(5 g5.(1181* 921 h5(0'02/(.@/(1 ',(17 81' ',( u3(=,77>7 '(5 -(:(,/,*(1 k*O 2'(5 vetOm(77( $860$&+7P f,( i(1( '(5 9(56&+,('(1(1 k*O 81' vetOm(77(1 6,1' $8) V e+5202620(1 9(57(,/7 81' (5675(&.(1 6,&+ -(:(,/6 @%(5 (,1( f,67$1= 921 TRR %,6 URRR m% Jc%%P UPVRKP f,( d(621'(5+(,7 ',(6(5 i(1/2&, %(67(+7 '$5,1N '$M ',( 9$5,$%/(1 m(77(1$17(,/( '85&+ =$+/5(,&+( i(16(*0(17( 5(35>6(17,(57 :(5'(1N ',( =81>&+67 '85&+ (,1( fpcOt(O .20%,1$7,21 =8 )81.7,2167@&+7,*(1 g,1+(,7(1 9(5.1@3)7 :(5'(1 0@66(1P f,(6(6 r5,1=,3 '(6 620$7,6&+(1 t($55$1*(0(176 921 fpcOu(48(1=(1 (50?*/,&+7 '(0 k008161*( =8 (,1(5 5(,)(1 0tpc :(,7(59(5$5%(,7(7 81' 6&+/,(M/,&+ ,1 (,1 r52O 7(,1 75$16/$7,(57P f,( WAOg;216 '(5 xOg/(0(17( .2',(5(1 ',( 62*(1$117(1 /($'(5JnKO u(48(1=(1P f$%(, +$1'(/7 (6 6,&+ 80 '(1 +6(17,(57P

UPW i(15(.20%,1$7,21 V

CACAGTG 12 Nukleotide

ACAAAAACC

Nonamer

Spacer (23)

5´ 3´

Heptamer

[Y J

3´ V

RSS

RSS

J

5´

RAG1+RAG2 V

J

signal joint

Ligase KU70/KU80 DNA-PKcs V

CCT G GGAC

Endonuklease, Polymerase Exonuklease, TdT V

CC GGACGT P

T GTC ACAG

J Deletion

+++ CCA TC GG T AG N

J

XRC4 Ligase4 V

CCTGCA CCA T C GGACGT GGT A G P N

J

coding joint

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SSR

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A T G

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C T

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DNA Polymerase ‰/Â PCNA RFC

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V o2/(.8/$50(',=,1,6&+( o(7+2'(1

6(48(1= =85 fpc t(3/,.$7,21 J6,(+( m$3P UPXPSK $/6 $8&+ c17,%,27,.$Ot(6,67(1=*(1( (17+$/7(1 Jc%%P VPSKP r/$60,'( .?11(1 6,&+ '$+(5 81$%+>1*,* 920 d$.7(5,(1&+52O 02620 $/6 *(1(7,6&+(6 g3,620 9(50(+5(1P f,( v(1'(1= '(5 |(//(N 1,&+7O(66(17,(//( fpc =8 (/,0,1,(5(1N .$11 '85&+ $17,%,27,6&+(1 u(/(.7,216'58&. @%(5:81'(1 :(5O '(1P Insertionsregion für exogene DNA von 87* %(187=7( d(O *5,5 '(5 fpcOm/21,(581* $%P q%6&+21 r/$60,'( ,0 r5,1=,3 $//( m5,7(5,(1 )@5 (,1 *((,*1(7(6 x(+,.(/ =85 fpcOm/21,(581* (5)@//(1 Jc%%P VPTKN :,5' ,+5 35$.7,6&+(5 g,16$7= 2)7 '$'85&+ %(*5(1=7N '$M 6,( =80 (,1(1 185 (7:$ 0$;,0$/ SR .% h5(0'O fpc $8)1(+0(1 .?11(1N 81' =80 $1'(5(1 ',( o(7+2'(1 =85 %$.7(5,(//(1 r/$60,'O v5$16)250$7,21 5(&+7 ,1(5(.7,9 6,1'P

SMPMPMQ a!+4%2)/0(!'%. x,5(1 6,1' %,2/2*,6&+ '$5$8) (,1*(67(//7N ,+5 *(1(7,6&+(6 o$7(5,$/ '85&+ k1)(.7,21 ,1 )5(0'( |(//(1 (,1=8%5,1*(1 J6,(+( m$3P YPTKP h@5 ',( fpcOm/21,(581* 6,1' d$.O 7(5,23+$*(1 '$+(5 2)7 (5,=,(17(5( x(.725(1 $/6 r/$60,'( Jc%%P VPSKP |80 %(66(5(1 x(567>1'1,6 ',(6(5 m/21,(581*6675$7(*,( 62// +,(5 .85= $8) '(1 k1)(.7,216=1*(1'(6 o2/(.@/ Jm21.$7(0(5K 5(3/,O =,(57N :2%(, ',( (,1=(/1(1 m23,(1 '85&+ 63(=,76&+( fpcOu(48(1=(1N '(1 62*(1$11O 7(1 &26Ou7(//(1N 921(,1$1'(5 $%*(*5(1=7 6,1'P f$5$8)+,1 :,5' '$6 m21.$7(0(5 $1 '(1 &26Ou7(//(1 *(63$/7(1 81' -(:(,/6 (,1 i(120 ,1 ',( )(57,*(1 j@//(1 9(53$&.7P n(7=7/,&+ 3/$7=7 ',( ,17=,(57( |(//( 81' 6(7=7 (,1( x,(/=$+/ 1(8(5 5(,)(5 d$.7(5,23+$*(1 )5(,N ',( -(7=7 6(/%67 :,('(5 12&+ 1,&+7 ,17=,(57( p$&+%$5=(//(1 ,17=,(5(1P k0 w17(5O 6&+,(' =8 '(1 r/$60,'(1 @%(575>*7 (,1 ,1.25325,(57(5 r+$*( .(,1( c17,%,27,.$5(6,O 67(1=P f,(6(6 u(/(.7,21635,1=,3 67(+7 '$0,7 $8&+ 1,&+7 =85 c15(,&+(581* 75$16)25O 0,(57(5 |(//(1 =85 x(5)@*81*P h@5 ',( w17(56&+(,'81* 921 5(.20%,1$17(1 *(*(1O @%(5 1$7,9(1 r+$*(1 0$&+7 0$1 6,&+ =8187=(N '$M '$6 r+$*(1*(120 (567(16 6(,1( (66(17,(//(1 i(1( $8) 185 .1$33 UR .% (17+>/7N 81' '$M =:(,7(16 185 62/&+( fpcO o2/(.@/( 9(53$&.7 :(5'(1 .?11(1N '(5(1 n>1*( 1,&+7 :(6(17/,&+ 921 '(5 1$7@5/,&+(1 i5?M( '(6 i(1206 '(6 +>87* 9(5:(1'(7(1 d$.7(5,23+$*(1 n$0%'$ 921 &$P VZ .% $%:(,&+7P |85 fpcOm/21,(581* ,1 r+$*(1 .?11(1 ',( 1,&+7O(66(17,(//(1 &$P SZ .% (17)(517 81' '85&+ (;2*(1( fpc (56(7=7 :(5'(1P f,( 5(.20%,1$17( fpc :,5' '$11 ,1 9,752 9(53$&.7 81' *((,*1(7( gP &2/, u7>00( 0,7 '(1 92//67>1',*(1 r+$O *(13$57,.(/1 ,17=,(57P f,( n>1*(163(=,77>7 '(6 x(53$&.81*60(&+$1,6086 %(:,5.7N '$M 1,&+7O5(.20%,1$17( r+$*(1Ofpc :(*(1 '(5 )(+/(1'(1 SZ .% 1,&+7 9(53$&.7 :(5'(1 .$11 81' 620,7 1,&+7 =85 k1)(.7,21 '(5 |(//(1 *((,*1(7 ,67P f(5 x257(,/ '(5 fpcOm/21,(581* ,1 r+$*(1 /,(*7 620,7 '$5,1N '$M ',( 0$;,0$/( n>1*( '(5 (;2*(1(1 fpc (7:$ '233(/7 62 *52M ,67 :,( %(, '(1 r/$60,'(1N 81' '$M gP &2/, |(//(1 '85&+ ',( k1)(.7,21 0,7 r+$*(1 :(,7$86 (5(.7,9(5 75$16)250,(57 :(5'(1 $/6 '85&+ (,1( 3$66,9( c8)1$+0( 921 r/$60,'(1P

SMPMPMR b/3-)$% g,1( +>87* %(187=7( '5,77( c/7(51$7,9( ,67 ',( x(5:(1'81* '(5 1$7@5/,&+(5:(,6( 1,&+7 925.200(1'(1 e260,'( $/6 x(.725(1 Jc%%P VPSKP g6 +$1'(/7 6,&+ +,(5%(, 80 r/$6O 0,'( 0,7 %$.7(5,(//(1 t(3/,.$7,21685635@1*(1 81' c17,%,27,.$Ot(6,67(1=*(1(1N ,1 ',( &26Ou(48(1=(1 $/6 u,*1$/(/(0(17( )@5 '(1 9,5$/(1 x(53$&.81*60(&+$1,6086 (,1O *(6(7=7 :85'(1P f,( (66(17,(//(1 d(67$1'7(,/( 62/&+(5 x(.725(1 6,1' 1,&+7 9,(/ 0(+5 $/6 W .% /$1*P f85&+ k1.25325$7,21 921 6 VR .% J81' ,0 62*(1$117(1 rS e260,' 921 %,6 =8 SRR .%K (;2*(1(5 fpc ,1 (,1 e260,' (1767(+7 (,1( t(.20%,1$17(N ',( ,1 9,752 ,1 r+$*(1+@//(1 9(53$&.7 81' =85 k1)(.7,21 921 gP &2/, %(187=7 :(5'(1 .$11P f$ e260,'( .(,1( i(1( )@5 9,5$/( j@//3527(,1( 2'(5 )@5 ',( t(*8/$7,21 '(6 9,5$/(1 k1)(.7,216=1*( '(5 ,1 (,1(5 |(//( ./21,(5%$5(1 fpc $8) (7:$ VR .%P c/O /(5',1*6 6,1' ',( *52M(1 e260,'( ,1 '(5 |(//( *(1(7,6&+ 1,&+7 62 67$%,/ :,( r+$*(1 2'(5 r/$60,'(N :$6 *(/(*(17/,&+ =8 t(.20%,1$7,21(1 '(5 ./21,(57(1 fpc )@+5(1 .$11P

VPS d$6,6:(5.=(8*(

SYU

SMPMPMS d802%33)/.36%+4/2%. y(11 0$1 1,&+7 185 ',( i(1$1$/+(5 (5/>87(57N %(1?7,*7 (,1 i(1 )@5 6(,1( g;35(66,21 $8M(5 '(1 r527(,1O.2',(5(1'(1 d(5(,&+(1 u7(8(5(/(0(17(P h@5 ',( g;35(66,21 (,1(6 (8.$5/7P f,( 0(,67(1 (176&+(,'(1'(1 fpcOg/(0(17( )@5 (,1( (5,=,(17( i(O 1(;35(66,21 ,1 gP &2/, /,(*(1 $/62 ,0 WÔd(5(,&+ '(6 i(16P f$+(5 :,5' ',( (;2*(1( fpc '(0 r5202725 (,1(6 gP &2/, i(16 0,7 (,1(0 2'(5 2+1( (,1(1 WÔv(,/ '(5 .2O ',(5(1'(1 u(48(1=(1 1$&+*(6&+$/7(7P j>87* :,5' +,(5 '$6 tOi$/$&726,'$6(*(1 JtO i$/K 9(5:(1'(7P p$&+ '(5 %$.7(5,(//(1 v5$16)250$7,21 (1767(+(1 '$11 h86,2163O 527(,1( 0,7 (,1(0 tOi$/ c0,12O 81' (,1(0 5(.20%,1$17(1 e$5%2;1.(1N 5(675,1*,(5(1N 0,7 '(5 (6 (,1 d$.7(5,80 ,17O =,(5(1 .$11P f(5 p$0( '(5 t(675,.7,216(1'218./($6(1 /(,7(7 6,&+ $86 ',(6(5 1$7@5O /,&+(1 h81.7,21 $%P f,( )@5 35$.7,6&+( |:(&.( +(5$865$*(1'( g,*(16&+$)7 '(5 t(675,.7,216(1'218.O /($6(1 ,67 ',( u3(=,77>7 ,+5(5 g5.(1181*66(48(1=(1 921 0(,67 9,(5 %,6 $&+7 d$6(1O 3$$5(1 n>1*( Jv$%P VPSN c%%P VPUKP f,(6 %('(87(7N '$M (,1 %(67,007(6 t(675,.7,21O Spaltung der beiden DNA Stränge an gegenüberliegenden Stellen 5´

G

G

G

C

C

C

3´

5´

G

G

G

3´

5´

C

C

C

3´

3´

C

C

C

G

G

G

5´

3´

C

C

C

5´

3´

G

G

G

5´

G

C

Smal Spaltung der beiden DNA Stränge an versetzten Stellen 5´

C

T

G

C

A

G

3´

5´

C

T

A

3´

G

A

C

G

T

C

5´

3´

G

5´ 3´

A

C

G

A

3´ 5´

G

3´

G

T

C

5´

T

C

C

3´

5´ 3´

G

5´

Pstl

5´

G

G

A

T

C

C

3´

5´

G

3´ 5´

3´

C

C

T

A

G

G

5´

3´

C

C

T

A

G

BamHl

c%%P VPU g1767(+81* 9(56&+,('(1(5 fpcOh5$*0(17(1'(1 1$&+ x(5'$8 0,7 817(56&+,('/,&+(1 v+,*.(,7 '(5 fpc 81' '(5 tpc =85 d$6(13$$581* =8187=(P y,( 6&+21 ,1 m$3,7(/ TPV '(7$,//,(57 (5/>87(57N 6,1' ',( %(,'(1 doppelsträngige DNA 3´ 5´

5´ 3´

Hitze- oder Alkalidenaturierung

radioaktiv markierte Gensonde

3´ 5´ 5´ einzelsträngige DNA

3´

5´ 5´

3´* 5´

3´* 5´

5´

3´*

3´*

3´*

Hybridisierung mit einem Überschuß an markierter Gensonde

3´ 5´

5´

3´*

5´ 3´

Autoradiographie

c%%P VPW u&+(0$7,6&+( f$567(//81* '(5 fpcOj1*( '(5 fpc f233(/+(/,; ,0 u,11( (,1(5 jM7 6,&+ (,1( j5=81* (,1(6 $8)*(/(*7(1 t?17*(17/06 ,1 '(5 62*(1$117(1 c8725$',2*5$3+,( 1$&+:(,6(1P d(621'(56 5(/(9$17( c1:(1'81*(1 '(5 fpc j87*67(1 $1*(:(1'(7( 02/(.8/$5O %,2/2*,6&+( w17(568&+81* ,1 '(5 35$.7,6&+O./,1,6&+(1 o(',=,1P u,( ',(17 =85 g5.(1O 181* 921 v5>*(51 9(5(5%7(5 g5.5$1.81*(1 62:,( =85 35>61'(581*(1 '(5 *(120,6&+(1 fpc =8/>M7P k0 i(*(16$7= '$=8 :,5' ',( 5(/$7,9 @%(56,&+7/,&+( *(120,6&+( fpc '(6 d$.7(5,23+$*(1 n$0%'$ 921 185 VZ .% '85&+ 9,(/( t(675,.7,216(1=1*,*( fpc =81>&+67 '85&+ (,1( c/.$/,%(+$1'/81* ,1 ,+5( g,1O =(/675>1*( =(5/(*7 81' '$11 '85&+ .$3,//$5( y,5.81* $/6 (;$.7( t(3/,.$ $8) (,1( 0(&+$1,6&+ 81' &+(0,6&+ 5(6,67(17( o(0%5$1 $86 p,752&(//8/26( 2'(5 p5%7(6 c*$526(*(/ 0,7 9(5'$8(5 *(120,6&+(5 fpcP f(5 h/825O (6=(1=)$5%6725 g7+,',80%520,' %,1'(7 6,&+ ,1 ',( fpcOf233(/+(/,;N 62 '$M fpc ,1 (,1(0 0,7 wxOn,&+7 75$16,//80,1,(57(1 i(/ 6,&+7%$5 :,5'P f,( 9,(/(1 +81'(577$86(1' %,6 (,1,*( o,/O /,21(1 817(56&+,('/,&+(1 h5$*0(17( '(5 9(5'$87(1 *(120,6&+(1 fpc 9(56&+:,00(1 '$%(, ,1 (,1(5 +202*(1 (56&+(,1(1'(1 u385P g,1 j,1' kkkOx(5'$8 921 n$0%'$Or+$*(1Ofpc (5*,%7 185 :(1,*( t(675,.7,216)5$*0(17( '(71,(57(5 i5?M(N ',( 620,7 $/6 n>1*(10$5.(5 (,1*(6(7=7 :(5'(1 .?11(1 JoN r)(,/(KP

kapillare Flußrichtung

VPT w17(568&+81* 921 fpc kg saugfähiges Filterpapier Nylonmembran Agarosegel saugfähiges Filterpapier Schale mit Puffer

c%%P VPY

SY[

Auflage

u&+(0$7,6&+( f$567(//81* (,1(5 u287+(51 d/27Oc33$5$785P

f(5 .5,7,6&+( u&+5,77 '(5 u287+(51 d/27Oc1$/7(5 %(,0 62*(1$117(1 675,1*(17(1 y$6&+(1 %(, +2+(5 v(03(5$785 81' 1,('5,*(5 u$/=O .21=(175$7,21 *(/?67 :(5'(1P f,( 0$5.,(57( i(1621'( %/(,%7 '$%(, '85&+ ',( y$6O 6(56725%5@&.(1%,1'81*(1 =:,6&+(1 '(1 .203/(0(17>5(1 p8./(27,'(1 63(=,76&+ $1 ,+5(5 |,(/6(48(1= +$)7(1N 62 '$M '85&+ c8725$',2*5$3+,( ',( r26,7,21 %=:P ',( n>1*( '(6 (17635(&+(1'(1 t(675,.7,216)5$*0(17(6 (50,77(/7 :(5'(1 .$11 Jc%%P VPZKP r5,O Agarosegel Agarosegel-GelElektrophorese

Restriktionsverdau

unverdaute chromosomale DNA

--

Auftragungsstelle

verdaute chromosomale DNA +

1

2

3 Southern BlotTransfer

Röntgenfilm

Nylonmembran Hybridisierung mit markierter Gensonde stringentes Waschen und Autoradiographie

1

2

3

1

2

3

c%%P VPZ u&+(0$7,6&+( f$567(//81* (,1(5 fpcOjM7 6,&+ $86 '(5 u287+(51 d/27Oc1$/5(B+202/2*( u(48(1=(1 0,7 '(5 u21'( d (17+$/7(1P f$6 g5*(%1,6 '(5 u287+(51 d/27Oc1$/1*7 620,7 921 '(5 9(5'$87(1 fpcN 921 '(0 9(5:(1'(7(1 g1=5,1)250$7,21 ,1 35$.7,6&+ 9(5:(57%$5( f,$*126(1 2'(5 02/(.8/$5O$1$720,O 6&+( g5.(1171,66( 80=86(7=(1 ,67P f,5(.7( g5.(1181* 921 r81.7087$7,21(1 y(11 x(5>1'(581*(1 '(5 p8./(27,'6(48(1= '$6 g5.(1181*66,*1$/ (,1(6 t(675,.O 7,216(1=1'(57( t(675,.7,216O P

V

M

F

SS

AA 1,4kb 1,2kb

Sonde normales ‚ Globingen

GAG

1,2kb

0,2kb

GTG

1,4kb

MstII Schnittstellen

Sichelzellgen

MstII Schnittstellen

c%%P VP[ u&+(0$7,6&+( 81' $8725$',2*5$3+,6&+( f$567(//81* '(5 f,$*126( '(5 u,&+(/=(//08O 7$7,21P p$&+ c*$526(Oi(/(/(.7523+25(6( 81' u287+(51 d/27Ov5$16)(5 o67 kk 9(5'$87(5 fpc ,'(17,7=,(57 (,1( i(1621'( $86 '(0 WAOd(5(,&+ '(6 tOi/2%,1*(16 %(, '(5 1250$/(1 fpc (,1 SNT .% 81' %(, '(5 3$7+2/2*,6&+(1 fpc (,1 SNV .% /$1*(6 h5$*0(17P f,( u,&+(/=(//087$7,21 Jici B iviK =(567?57 ',( o67 kk t(675,.7,21667(//( ,0 e2'21 X '(6 tOi/2%,1*(16P f,( c8725$',2*5$3+,( =(,*7 (,1( r5>1$7$/',$*126(N ',( %(,0 h(786 (,1(1 +202=M7 6,&+ -('2&+ $8&+ (,1( 0?*/,&+( h(+/(548(//( %(, '(5 k17(535(7$7,21 (,1(5 fpcOc1$/0,(087$7,21 $1 '(5 */(,&+(1 u7(//( JWÔ eev iOi iciOU^KP k1 '(5 fpcOc1$//7,*( 3+>1271*(1Or2/87(57 :(5'(1P g6 817(56&+(,'(1 6,&+ +,(5%(, 1,&+7 185 ',( 0(',=,1,6&+(1

SZT

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

h5$*(67(//81*(1 621'(51 $8&+ ',( 02/(.8/$5%,2/2*,6&+(1 u75$7(*,(1 '(5 fpcOc1$O ///(1 '$11 $8&+ (,1,*( '(5 )@5 '$6 m5$1.+(,76%,/' 9(5$17:257O /,&+(1 o87$7,21(1P c//(5',1*6 ,67 ',( 02/(.8/$5( r$7+2/2*,( 7527= '(5 +(87( 9(5)@*O %$5(1 v(&+12/2*,( =85 u(48(1=,(581* 2)7 =8 .203/(;N 80 ,1 -('(0 ,1',9,'8(//(1 h$// '(1 (;$.7(1 i(1'()(.7 )@5 ',$*1267,6&+( |:(&.( %(67,00(1 =8 .?11(1P d(,O 63,(/( 71'(1 6,&+ +,(5 %(, '(1 j>023+,/,(1 81' %(, '(5 o86.(/'+( (,1(6 5(/(9$17(1 i(1/2&86 J6&+:$5=(6 t(&+7(&.K %(71'(1 6,&+ t(675,.7,21667(//(1 (,1(6 %(67,007(1 g1=1$7$/(1 f,$*1267,. =80 c866&+/8M '(6 i(1271*7 920 $1$720,6&+(1 c%67$1' =:,6&+(1 '(0 o$5.(5/2&86 81' '(0 i(1/2&86 %=:P 921 '(5 p(,*81* '(5 %(7(,/,*7(1 fpcOc%O 6&+1,77( =85 t(.20%,1$7,21 $%P l( :(,7(5 o$5.(5 81' i(1 $86(,1$1'(5 /,(*(1 81' -( +?+(5 ',( t(.20%,1$7,2165$7( ,1 ',(6(0 d(5(,&+ ,67N '(672 6&+/(&+7(5 ,67 '(5 o$5O .(5 )@5 ',$*1267,6&+( |:(&.( *((,*1(7P i87( o$5.(5N :,( 6,( '85&+ ',( h2576&+5,77( '(6 j80$1*(120352-(.7(6 J6,(+( m$3P VPZK ,1=:,6&+(1 )@5 ',( 0(,67(1 g5.5$1.81O *(1 =85 x(5)@*81* 67(+(1N +$%(1 (,1( t(.20%,1$7,2165$7( 0,7 '(0 i(1/2&86 921 1,&+7 0(+5 $/6 S@P f,( ',$*1267,6&+( u,&+(5+(,7 /,(*7 '$11 %(, [[ @P f,( ',$*1267,6&+( u,&+(5+(,7 327(1=,(57 6,&+ '85&+ ',( x(5:(1'81* 921 o$5.(5/2&, $8) %(,'(1 u(,7(1 '(6 i(16P k1 '(0 +,(5 *(=(,*7(1 d(,63,(/ Jc%%P VPSRK /,(*7 '(5 o$5.(5/2&86 U $8) '(5 $1'(5(1 u(,7( '(6 i(16 $/6 '(5 o$5.(5/2&86 T 81' +$7 ',( $//(/(1 h250(1 $ 81' %P k1 '(5 h$0,/,( ,67 '$6 3$7+2/2*,6&+( c//(/ r '(6 i(1/2&86

rekombinierte Chromosomen in den Keimzellen

Crossing-over bei der Paarung der homologen Chromosomen während der Meiose

Allel A

Allel P

Allel a

Allel A

Allel P

Allel a

Allel B

Allel N

Allel b

Allel B

Allel N

Allel b

Allel A

Allel P

Allel a

Allel A

Allel N

Allel b

Allel B

Allel P

Allel a

Allel B

Allel N

Allel b

c%%P VPSU u&+(0$7,6&+( f$567(//81* (,1(6 e5266,1*O29(5 =:,6&+(1 '(0 i(1/2&86 81' '(1 32/+5(1' '(5 o(,26( 5(.20%,1,(57 ',( m233/81* '(5 c//(/( '(6 i(1/2&86 0,7 '(1 o$5.(5/2&, 81' .$11 62 =8 h(+/',$*126(1 )@+5(1P

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7(5,$/ $/6 )@5 ',( &fpcOm/21,(581*P |,(/ ,67 (6 +,(5N '$6 *(6$07( 2'(5 (,1(1 '(71,(57(1 v(,/ '(6 i(1206N 81*($&+7(7 921 '(66(1 g;35(66,21 ,1 (,1(5 i(1%$1. $1=8/(*(1 81' ',( *(:@16&+7(1 u(48(1=(1 =8 ,'(17,7=,(5(1 81' =8 ,62/,(5(1P c/6 c86*$1*60$7(5,$/ ',(17 *(120,6&+( fpcN ',( 35,1=,3,(// $86 (,1(0 %(/,(%,*(1 i(:(%( ,1 0?*/,&+67 +2&+02/(.8/$5(5 h250 *(:211(1 :,5'P f$=8 :(5'(1 ',( |(/O /(1 =81>&+67 0,7 (,1(0 f(7(5*(1= ///7 Jc%%P VPUSKP x(.725(1 =85 fpcOm/21,(581* .?11(1 185 %(*5(1=7( o(1*(1 (;2*(1(5 fpc $8)1(+0(1 Jc%%P VPSKP f,( *(120,6&+( fpc 08M '$+(5 ,1 h5$*0(17( (,1(5 $8) '(1 x(.725 $1*(3$M7(1 n>1*( =(5/(*7 :(5'(1P f,(6 .$11 $0 %(67(1 '85&+ (,1(1 3$57,(//(1 x(5'$8 0,7 (,1(0 +>87* 6&+1(,'(1'(1 t(675,.7,216(1=1',*(1 u3$/781* 0,7 (,1(0 6(/7(1(5 6&+1(,'(1'(1 g1=+/7(1 x(.725 /,*,(57 81' =85 v5$16)250$7,21 %(187=7 :(5'(1P g,1( i(1%$1.N 'P +P ',( i(6$07+(,7 $//(5 5(.20%,1$17(1 m/21(N ',( '$6 *(6$07( ',3/2,'( i(120 921 (7:$ X4SR[ %3 %(,63,(/6:(,6( ,1 (,1(0 e26O 0,'9(.725 5(35>6(17,(5(1 62//N 08M $/62 5(&+1(5,6&+ SNW4SRW t(.20%,1$17(1 0,7 VR .% (;2*(1(5 fpc (17+$/7(1P g5)$+581*6*(0>M %(1?7,*7 0$1 )@5 (,1( 6,&+(5 5(35>6(17$7,9( i(1%$1. $//(5',1*6 (7:$ =:(,O %,6 '5(,0$/ 629,(/( t(.20%,1$17(1 %=:P 75$16)250,(57( gP &2/, m/21(P |85 k'(17,7.$7,21 '(6 *(:@16&+7(1 h5$*0(17(6 .$11 0(,67 ',( =8*(+?5,*( &fpc 2'(5 0$1&+0$/ (,1( %(.$117( u(48(1= ,1 '(5 810,77(/%$5(1 p$&+%$56&+$)7 %(187=7 :(5'(1 Jc%%P VPUTN c%%P VPUUKP

c%%P VPUT h272 (,1(5 c*$53/$77( 0,7 d$.7(5,(1.2/21,(1 $/6 v(,/ (,1(5 i(1%$1. J$KP c872O 5$',2*5$3+,( 1$&+ u&5((1,1* '(5 i(1%$1. 0,7 (,1(5 i(1621'(P f,( *(68&+7(1 m/21( :(5'(1 1$&+ 63(=,76&+(5 j//(1 (50?*/,&+7 ',( u75$7(*,( '(6 62*(1$117(1 NN&+5202620( :$/.,1*DD (,1( m/21,(581* =86$00(1+>1*(1'(5 *(120,6&+(5 fpc Jc%%P VPUVKP c/6 c86*$1*6381.7 %(1?7,*7 0$1 (,1 5(.20%,1$17(6 e260,' 2'(5 d$.7(5,23+$O *(1N '(5 %(,63,(/6:(,6( 0,7 (,1(5 &fpc '(6 817(568&+7(1 i(16 $/6 u21'( $86 (,1(5 *(120,6&+(1 i(1%$1. ,62/,(57 :85'(P f$6 &+5202620( :$/.,1* (5/$8%7 181N @%(5O /$33(1'( m/21( $8) %(,'(1 u(,7(1 '(6 c86*$1*6./216 =8 ,62/,(5(1P f$=8 68&+7 0$1 ,1 '(0 925/,(*(1'(1 m/21 1$&+ 6,1*/( &23< u(48(1=(1N ',( '$11 $/6 u21'( )@5 (,1(1 (51(87(1 |8*$1* ,1 ',( i(1%$1. ',(1(1P f,( d(6&+5>1.81* $8) 6,1*/( &23< u(48(1O =(1 $/6 u21'( ,67 :,&+7,*N :(,/ h5$*0(17( 0,7 5(3(7,7,9(1 u(48(1=(1 m/21( 0,7 6(+5 817(56&+,('/,&+(5 *(120,6&+(5 n2.$/,6$7,21 (5.(11(1 :@5'(1P f,( k'(17,7=,(581* 5(3(7,7,9(5 u(48(1=(1 ,1 (,1(5 t(.20%,1$17( .$11 '85&+ (,1( u287+(51 d/27Oc1$O /M7 6,&+ '85&+ t(675,.7,2169(5'$8 '(5 9(56&+,('(1(1 t(O .20%,1$17(1 $%6&+>7=(1P y,('(5+2/81*(1 ',(6(6 u&+5,77(6 '(6 &+5202620( :$/.,1* )@+5(1 =85 m/21,(581* (,1(5 6,&+ 1$&+ %(,'(1 u(,7(1 '(6 c86*$1*6./216 $86'(+1(1'(1 =86$00(1+>1*(1O '(1 t(*,21 *(120,6&+(5 fpcN (,1(6 62*P e217,*6P c8) ',(6( y(,6( .?11(1 620,7 $8&+ *5?M(5( i(1( 0,76$07 k175216 81' 1,&+7 75$16.5,%,(57(1 t(*8/$7,216(/(0(17(1 92//67>1',* ./21,(57 :(5'(1P o,7 -('(0 u&+5,77 '(6 &+5202620( :$/.,1*6N ',( -(:(,/6 ,17(16,9( n$%25$5%(,7 (5)25'(51N %(:(*7 0$1 6,&+ 0$;,0$/ VR .% $8) '(0 e+5202620 925:>576P d(, (,1,O *(1 c1:(1'81*(1N :,( (7:$ %(, '(5 r26,7,216./21,(581* J6,(+( m$3P VPYKN 0@66(1 817(5 w067>1'(1 (,1,*( +81'(57 .% @%(5:81'(1 :(5'(1N 80 921 (,1(0 i(10$5.(5 =80 i(1 6(/%67 =8 .200(1P k1 ',(6(1 h>//(1 ,67 '$6 &+5202620( :$/.,1* 6&+21 :(*(1 6(,1(5 *(5,1*(1 i(6&+:,1',*.(,7 (,1( 185 6&+:(5/,&+ 35$.7,.$%/( u75$7(*,(P c8M(5'(0 (17+>/7 '$6 0(16&+/,&+( i(120 u(48(1=(1N ',( $86 817(56&+,('/,&+(1 i5@1'(1 1,&+7 ./21,(5%$5 6,1'P u2/&+( u(48(1=(1 .?11(1 (,1(1 &+5202620( :$/. '85&+$86 67233(1 81' (,1( e+$5$.7(5,6,(581* '(5 fpc -(16(,76 (,1(5 62/&+(1 t(*,21 9(5+,1'(51P d(,'( r52%/(0( /?67 ',( 7(&+1,6&+ $//(5',1*6 6(+5 $16358&+692//( u75$O 7(*,( '(6 NN&+5202620( -803,1*6DD Jc%%P VPUWKP

TTT

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

partieller Verdau mit dem 1. Restriktionsenzym und Größenselektion

genomische DNA

mehrere hundert kb

Selektionsmarker

DNA-Ligierung

vollständige Spaltung mit dem 2. Restriktionsenzym

wenige kb Transformation „Jumping“ Genbank „Screening“ isolierte „Jumping“ Klone

c%%P VPUW u&+(0$7,6&+( f$567(//81* '(6 &+5202620( -803,1*P p$&+ 3$57,(//(0 t(675,.O 7,2169(5'$8 (1767(+(1 0(+5(5( +81'(57 .% *52M( fpcOh5$*0(17(N ',( 817(5 g,16&+/8M (,1(6 u(/(.7,2160$5.(56 =81>&+67 =,5.8/$5,6,(57 :(5'(1P k1 (,1(0 =:(,7(1 u&+5,77 :,5' (,1 :(1,*( .% *52M(6 fpcOh5$*0(17 ./21,(57N '$6 1(%(1 '(0 u(/(.7,2160$5.(5 u(48(1=(1 (17+>/7N ',( ,0 i(120 (,1,*( +81'(57 .% 921(,1$1'(5 (17)(517 $8) '(06(/%(1 e+5202620 /,(*(1P f,( =:,6&+(1 ,+1(1 /,(*(1'( fpc :,5' '$%(, NN@%(563581*(1DDP

f$%(, :(5'(1 /$1*( *(120,6&+( fpcOh5$*0(17( 921 %(,63,(/6:(,6( SWR .%N ',( (17:('(5 '85&+ (,1(1 3$57,(//(1 x(5'$8 0,7 (,1(0 +>87* 6&+1(,'(1'(1 2'(5 '85&+ 92//67>1',*( u3$/781* 0,7 (,1(0 6(/7(1 6&+1(,'(1'(1 t(675,.7,216(1=&+67(1 u&+5,77 :,5' '(5 fpcOt,1* 0,7 (,1(0 =:(,7(1 t(675,.7,216(1=/7 $/62 t(.20%,1$17(1N '(O 5(1 (;2*(1( u(48(1=(1 ,1 '(5 *(120,6&+(1 fpc :(,7 921(,1$1'(5 (17)(517 $%(5 $8) '(0 6(/%(1 e+5202620 /,(*(1'( fpc (17+$/7(1P c86*(+(1' 921 (,1(5 %(.$11O 7(1 u(48(1= .$11 0$1 62 ,1 '(5 :(,7(5(1 p$&+%$56&+$)7 /,(*(1'( h5$*0(17( ,62O /,(5(1N .$57,(5(1 81' &+$5$.7(5,6,(5(1P o,7 '(0 &+5202620( -803,1* (55(,&+7 0$1 620,7 (,1( +?+(5( i(6&+:,1',*.(,7 '(5 e+$5$.7(5,6,(581* *5?M(5(5 c%6&+1,77( (,1(6 e+52026206 81' .$11 '$5@%(5 +,1$86 1,&+7 ./21,(5%$5( u(48(1=(1 @%(5635,1*(1P f85&+ &+5202620( -803,1* ,62O /,(57( m/21( .?11(1 :(,7(5+,1 $/6 u7$57381.7( )@5 (,1 &+5202620( :$/.,1* $8) '(5 %(1$&+%$57(1 fpc ',(1(1P c/6 :2+/ %,6+(5 :,&+7,*67( 0(',=,1,6&+( c1:(1'81* *(/$1* '85&+ (,1( m20%,1$7,21 921 &+5202620( :$/.,1* 81' -803,1* ',( k'(1O 7,7.$7,21 '(6 i(1'()(.7(6 %(, '(5 o8.29,6=,'26(P

SMV f%.+!24)%25.' 5.$ f%.)$%.4)&):)%25.' f,( 02/(.8/$5( c1$/581* '(5 02/(.8/$5(1 r$7+2/2*,( +(5(',7>5(5 81' (5:25%(1(5 g5O .5$1.81*(1 .2117( ,1 9,(/(1 h>//(1 (,1 x(567>1'1,6 '(5 *581'/(*(1'(1 r$7+2*(1(6( (55(,&+7 :(5'(1P k1 (,1,*(1 h>//(1 :$5 ',(6 $8&+ (,1 (567(5 c16$7=381.7 )@5 ',( g17:,&./81* 1(8(5 2'(5 9(5%(66(57(5 .219(17,21(//(5 v+(5$3,()250(1P j,(5 62//(1 9(56&+,('(1( u75$7(*,(1 =85 m$57,(581*N k'(17,7=,(581* 81' e+$5$.7(5,6,(581* 921 0(16&+/,&+(1 i(1(1 (5/>87(57 :(5'(1 Jc%%P VPUXKP f$6 0(16&+/,&+( i(120 (17+>/7 (7:$ SVRPRRR i(1(P f(0*(*(1@%(5 6,1' 185 (7:$ YPRRR +(5(',7>5( m5$1.+(,7(1 '(6 o(16&+(1 .$7$/2*,6,(57 Jo&m86,&.I6 o(1O '(/,$1 k1+(5,7$1&( ,1 o$1KP f,(6( f,6.5(3$1= ,67 =80 (,1(1 '$'85&+ (5./>5%$5N '$M %(, 9,(/(1 g5.5$1.81*(1 (,1( *(1(7,6&+( m20321(17( +(87( 12&+ 1,&+7 (7$%/,(57 ,67P |80 $1'(5(1 ,67 =8 (5:$57(1N '$M 9,(/( i(1( ,0 i(120 +,16,&+7/,&+ ,+5(5 h81.7,21 5('81'$17 6,1' 81' $1'(5( i(1352'8.7( (,1(1 0?*/,&+(1 f()(.7 .203(16,(5(1 .?11(1P c8&+ *,%7 (6 i(1'()(.7(N ',( 6,&+ %(5(,76 ,1 '(5 g0%5/71,6 :,5' $8&+

TTV

V o2/(.8/$50(',=,1,6&+( o(7+2'(1 Positionsklonierung

funktionelle Klonierung

reverse Genetik

Phänotyp

bekannter biochemischer Defekt (Enzym)

Gen mit unbekannter Funktion

genetische Kartierung

Isolation des Gens

in vitro Mutagenese

Isolation des Gens

Identifizierung von Mutationen

Phänotyp

Identifizierung von Mutationen

Funktionsanalyse

c%%P VPUX u75$7(*,(1 =85 c1$/7(5 $8&+ ',( .203/(;(5(1 08/7,)$.725,(//(1 m5$1.+(,7(1 9(5O 67(+(1 =8 .?11(1P

SMVMP j!24)%25.' -/./'%.%2 d2+2!.+5.'%. c/6 (567(5 u&+5,77 =85 k'(17,7=,(581* 921 i(1(1 08M 0(,67 '(5 i(1257 ,0 i(120 .$57,(57 :(5'(1P x(5*/(,&+6:(,6( (,1)$&+ ,67 ',( m$57,(581* ,1 h>//(1 0,7 :(*:(,O 6(1'(1 &//,*(1 d()81'(1N :,( (7:$ v5$16/2.$7,21(1N ',( (,1(1 ',O 5(.7(1 g,167,(* ,1 ',( r26,7,216./21,(581* '(6 5(/(9$17(1 i(16 (5/$8%(1 J6,(+( m$3P VPYPWKP k1 $1'(5(1 h>//(1 08M ',( &+5202620$/( u8%/2.$/,6$7,21 '(6 *(68&+7(1 i(16 =81>&+67 '85&+ (,1( m233/81*6817(568&+81* 0,7 32/1*7N 2% '(5 32/M,* 9(57(,/7 6(,1 .?11(1P f$+(5 6,1' 9,(/( o,7*/,('(5 (,1(6 u7$00%$806 )@5 ',( 0(,67(1 thnr6 +202=7=/,&+(1 r$5$0(7(5 (5*,%7 (,1( m233/81*6$1$/+5(1' '(5 o(,26( =85 t(.20%,1$7,21 81' '$'85&+ =85 v5(1181* 921 925+(5 *(.233(/7(1 c//(/(1P f(5 c%67$1' =:,6&+(1 '(1 n2&, .$11 620,7 ,1',5(.7 @%(5 ',( 62*(1$117( t(.20O %,1$7,216)5$.7,21 '(71,(57 :(5'(1P g,1( t(.20%,1$7,216)5$.7,21 921 RNRS *,%7 $/62 $1N '$M (6 ,1 S@ '(5 o(,26(1 =85 t(.20%,1$7,21 .2007 JS &(17,Oo25*$1N &oKP f,( 0$;,0$/( t(.20%,1$7,216)5$.7,21N (7:$ 921 =:(, $8) 817(56&+,('/,&+(1 e+52O 02620(1 /2.$/,6,(57(1 n2&,N %(75>*7 RNWP f,( d(67,0081* '(5 t(.20%,1$7,216)5$.O 7,21 />M7 6,&+ :(*(1 '(5 6(+5 817(56&+,('/,&+(1 t(.20%,1$7,2161(,*81* 9(56&+,(O '(1(5 u(48(1=$%6&+1,77( 185 %(',1*7 ,1 (,1(1 7$76>&+/,&+(1 3+M7P f,(6 80)$M7 $//(5',1*6 12&+ ,00(5 (,1( fpcO t(*,21 921 &$P WPRRR .%P f,( *(1$8( g,1*5(1=81* '(6 m233/81*6,17(59$//6 ,67 (,1( :(6(17/,&+( x25$866(7=81* =85 k62/,(581* '(6 *(68&+7(1 i(16P l( 1$&+ i5?M( ',(6(6 k17(59$//6 .$11 ',(6 81' '(5 $16&+/,(M(1'( p$&+:(,6 921 o87$7,21(1 %(, %(7525(1(1 r$7,(17(1 0(+5(5( l$+5( ,1 c16358&+ 1(+0(1P d(, '(5 o8.29,6=,'26( /$*(1 =:,6&+(1 '(5 *(1(7,6&+(1 m$57,(581* ,0 l$+5( S[ZW 81' '(5 k62/,(581* '(6 i(16 S[Z[ 9,(5 l$+5(N %(, '(5 o86.(/'87*(1 g5.5$1.81*(1 1>+(5=8.200(1N ,67 ',( k'(17,7.$7,21 921 i(1(1N ',( ,1 '(0 .203/(;(1 p(7=:(5. (,1(5 32/581* '(5 h81.7,21 (,1=(/1(5 i(1( 81' '(5 3$7+2*(1(7,6&+(1 |86$00(1+>1*( 921 g,1=(/*(1'()(.7(1 $8&+ %(, '(1 .20O 3/(;(1 g5.5$1.81*(1 :(,7(5+(/)(1 :,5'P

SMVMR h$%.4)&):)%25.' 6/. f%.%. $52#( &5.+4)/.%,,% j,/.)%25.' f,( )81.7,21(//( m/21,(581* 921 i(1(1 6(7=7 ',( m(1171,6 @%(5 '(1 35,0>5(1 %,2O &+(0,6&+(1 f()(.7 925$86P o,7 j,/)( 02/(.8/$5*(1(7,6&+(5 o(7+2'(1 .$11 '$11 '$6 .255(6321',(5(1'( i(1 ,62/,(57 :(5'(1P f,(6( u75$7(*,( :85'( (7:$ =85 k'(1O 7,7=,(581* '(5 i(1( )@5 ',( j>023+,/,(1 2'(5 '(5 r+(187(57 :(5'(1P f,( j>023+,/,( c ,67 (,1( zO&+5202620$/ 5(=(66,9 9(5(5%7( g5.5$1.81*N ',( '85&+ o87$7,21(1 ,0 i(1 )@5 '(1 d/87*(5,1181*6)$.725 xkkk JhxkkkK 9(5856$&+7 :,5'P g,1 (176&+(,'(1'(5 u&+5,77 )@5 ',( k62/,(581* '(6 hxkkkOi(16 :$5 ',( k62/,(581* 81' t(,1,*81* '(6 r527(,16 $86 '(0 r/$60$ 921 *(681'(1 r(5621(1P o,7 %,2&+(O 0,6&+(1 o(7+2'(1 .2117( ',( c0,126>85(6(48(1= (,1(6 v(,/6 ',(6(6 *52M(1 r527(,16 %(67,007 :(5'(1P c8) '(5 d$6,6 '(6 *(1(7,6&+(1 e2'(6 J6,(+( m$3P UPVPTK .2117(1 '$5$8)+,1 i(1621'(1 67(5 '(5 *(120,6&+(1 fpc *(/$1*P k0 c16&+/8M .2117( %(, r$7,(17(1 0,7 (,1(5 j>023+,/,( c 687*( 3$57,(//( i(1,19(56,21 )(67*(67(//7 :(5O '(1N ',( '85&+ +202/2*( fpcOc%6&+1,77( ,11(5+$/% '(5 r52027255(*,21 81' ,0 k17521 TT 9(5856$&+7 :,5'P f,(6( i(1,19(56,21 :85'( %(, 0(+5 $/6 VR@ '(5 %(621O '(56 6&+:(5 %(7525(1(1 r$7,(17(1 1$&+*(:,(6(1P p(%(1 '(5 m(1171,6 @%(5 ',( o87$7,21(1 0,7 '(1 '$5$86 5(68/7,(5(1'(1 ',$*1267,6&+(1 o?*/,&+.(,7(1N =80 d(,O 63,(/ =85 k'(17,7=,(581* 921 m21'8.725,11(1N :$5 ',( m/21,(581* '(6 hxkkkOi(16 (,1( (176&+(,'(1'( x25$866(7=81* )@5 ',( *(17(&+1,6&+( j(567(//81* ',(6(6 r527(,16 J6,(+( m$3P ZPSKP f,( .$7$67523+$/(1 h2/*(1 '(5 c33/,.$7,21 jkxO 81' j(3$7,7,6O

VPY i(1.$57,(581* 81' i(1,'(17,7=,(581*

TT[

,17=,(57(5 .219(17,21(// +(5*(67(//7(5 r5>3$5$7( 9(5'(87/,&+(1 ',( *$1= 35$.7,6&+(1 k03/,.$7,21(1 ',(6(5 u75$7(*,(P f,( r+(1%&+(1 '(5 p(7=+$87P d(, '(5 (5%/,&+(1 p(7=+$87'(*(1(5$7,21 Jt(7,1,7,6 3,*0(1726$] trK .2007 (6 %(, '(1 %(7525(1(1 r$7,(17(1 =80 925=(,7,*(1 c%67(5%(1 '(5 r+2725(=(3725=(//(1 ,1 '(5 p(7=+$87 81' 6&+/,(M/,&+ =85 9?//,*(1 g5O %/,1'81* '(6 r$7,(17(1 ,1 '(5 UP %,6 VP n(%(16'(.$'(P f,( *(1(7,6&+( m233/81*6$1$O /1*,* '$921 :$5 '$6 t+2'236,1*(1 ,1 '(56(/%(1 t(*,21 JU4TSO4TVK .$5O 7,(57 :25'(1P t+2'236,1 *(+?57 =8 '(5 m/$66( 921 v5$160(0%5$1Ot(=(3725(1 81' 67(+7 ,1 '(5 p(7=+$87 $0 c1)$1* (,1(5 u,*1$/75$16'8.7,216.$6.$'(N ',( n,&+7O ,1 &+(0,6&+( t(,=( 80:$1'(/7P i581'6>7=/,&+ :$5 (,1 t+2'236,1'()(.7 %(, '(5 tr $/62 *87 92567(//%$5N 81' '$6 t+2'236,1*(1 5(35>6(17,(57( '$+(5 (,1 7&+67 .(,1( t2//(P f,( r26,7,216./21,(581* :85'( (5670$/6 (5)2/*5(,&+ S[ZX %(, '(5 e+521,6&+(1 i5$18/20$726( $1*(:$1'7N ',( (567 62 $/6 i(1'()(.7 '(6 e//(1 .2117(1 '$O '85&+ (176&+(,'(1'( m(1171,66( @%(5 ',( d,2&+(0,( 81' ',( r$7+2*(1(6( *(:211(1 :(5'(1P

22.3

Kopplungsintervall

22.2 22.1

Suche nach strukturellen Chromosomenveränderungen (z.B. Deletionen)

Identifizierung von Genen

Mutationsanalyse

21.1 11.4 11.3 11.23 11.22 cen

Kontrolle

21.3

Kontrolle

Xp

Assemblierung überlappender genomischer DNA-Fragmente in contigs

Patienten

Patienten 1 2 3 4 5 6

12

Mutationen

13 21.1

SSCP-Analyse

21.3

Xq

22.1 22.3 23

Southern-Blot-Analyse

24 25 26 27

-2.000 kbp

50 – 500 kbp

1– 200 kbp

einzelne Basenpaare

28

genetische Karte

physikalische Karte

Gen (Transkriptions)-Karte

DNA-Sequenzanalyse

c%%P VPU[ u&+(0$7,6&+( f$567(//81* '(5 9(56&+,('(1(1 v(,/6&+5,77( '(5 r26,7,216./21,(581* $0 d(,63,(/ (,1(6 zO&+5202620$/(1 i(16P c86*$1*6381.7 ,67 ',( f(71,7,21 '(6 m233/81*6O ,17(59$/6 0,7 j,/)( *(1(7,6&+(5 o$5.(5P c16&+/,(66(1' (5)2/*7 ',( c66(0%/,(581* (,1=(/1(5 fpcOh5$*0(17( ,1 (,1(0 e217,*P g,1(6 ',(6(5 h5$*0(17( '(7(.7,(57 f(/(7,21(1 Jx(5/867 921 *(1(7,6&+(0 o$7(5,$/K %(, (,1(0 v(,/ '(5 r$7,(17(1P f,( $16&+/,(66(1'( o87$7,216$1$/1'(57(1 n$8)9(5O +$/7(1 >866(51P

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TUS

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SMXMPMQ j,!33)3#(% l54!'%.%3% e+(0,6&+( c*(1=,(1 :,( g7+1*,* 921 '(5 9(5:(1'(7(1 e+(0,.$/,(P gpw %(:,5.7 ',6.5(7( n>6,21(1 81' r81.7087$7,21(1P h@5 ',( y,5.81*6817(56&+,('( '(5 9(56&+,('(1(1 c*(1=,(1 ,67 1,&+7 ',( &+(0,6&+( u758.785 '(6 o87$*(16 6(/%67 9(5$17:257/,&+N 621'(51 ',( v$7O 6$&+(N '$M 6,( =8 817(56&+,('/,&+(1 u78)(1 '(5 u3(50$72*(1(6( $.7,9 6,1'P gpw ,67 (,1( '(5 67>5.67(1 087$*(1(1 u8%67$1=(1 81' '$+(5 (,1( u&+/@66(/68%O 67$1= )@5 ',( (5,=,(17( r52'8.7,21 921 &+(0,6&+ ,1'8=,(57(1 o87$17(1 ,1 '(5 o$86P f$ ',( 5(,1( u(48(1=,1)250$7,21 .(,1( c17:257(1 =85 i(1)81.7,21 /,()(57N (5/(%7 ',( gpw o87$*(1(6( *(5$'( ,0 |86$00(1+$1* 0,7 '(0 j80$1*(120352-(.7 J6,(+( m$3P VPZK (,1( 1(8( }5$P c8)*581' ,+5(5 x257(,/( $/6 o2'(//61'(581*(1 %(, o>86(1 .?11(1 '85&+ (,1( 81*(5,&+7(7( k17(*5$7,21 (;2*(1(5 fpcN (,1(6 62*(1$117(1 v5$16*(16N 925*(1200(1 :(5'(1P f,(6( o>86( :(5'(1 (17635(&+(1' $/6 75$16*(1( o>86( %(=(,&+1(7P c8M(5'(0 .?11(1 $8&+ =,(/O *(5,&+7(7( o87$7,21(1 63(=,76&+(5 i(1( *(1(5,(57 :(5'(1N ',( -( 1$&+ o87$7,21671'(57( o>86(P v5$16*(1( o>86( ,0 (1*(5(1 u,11( :(5'(1 '85&+ x25.(51,1-(.7,21 921 /,1($5(1 fpcOm216758.7(1 ,1 %()58&+7(7( g,=(//(1 (5=(8*7N ',( $86 '(0 g,/(,7(5 921 :(1,*( u781'(1 6&+:$1*(5(1 u3(1'(57,(5(1 35>3$5,(57 :(5'(1P f$6 fpcOm216758.7 (17O +>/7 ,0 $//*(0(,1(1 '$6 v5$16*(1N %(67(+(1' $86 (,1(5 .2',(5(1'(1 u(48(1= )@5 (,1 r527(,1 81' ',( =8 6(,1(5 g;35(66,21 1?7,*(1 5(*8/$725,6&+(1 g/(0(17( Jc%%P VPVT $KP n(7=7(5( .?11(1 (1'2*(1( u(48(1=(1 2'(5 g/(0(17( $1'(5(5 i(1( 6(,1P f$6 v5$16*(1 ,16(5,(57 ,1 $//(5 t(*(/ 67$%,/ $1 0,1'(67(16 (,1(0 q57 ,0 i(120 Ji(1/2&86KN +>87* 0,7 0(+5(5(1 m23,(1 JSASRRKP o,7 ',(6(0 c16$7= .$11 ',( g;O 35(66,21 (1'2*(1(5 i(1( ,1 c%+>1*,*.(,7 '(5 9(5:(1'(7(1 r5202725(1 48$17,7$7,9N 2172*(1(7,6&+ 2'(5 *(:(%(63(=,76&+ 5(*8/,(57 :(5'(1P g%(162 .?11(1 x$5,$17(1 (1'2*(1(5 i(1( 2'(5 i(1( $1'(5(5 u3(=,(6 (;35,0,(57 :(5'(1P h@5 NN*(1( 5(3$,5DD

TVR

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

w17(568&+81*(1 Jm203/(0(17$7,216$16$7=K .?11(1 ,17$.7( i(1( ,1 (,1(0 087$1O 7(1 o$8667$00 (;35,0,(57 :(5'(1P g,1 x257(,/ ',(6(5 o(7+2'( *(*(1@%(5 '(5 817(5 .12&.O,1 o87$17(1 J6,(+( 817(1K %(6&+5,(%(1(1 o(7+2'( ,67N '$M .(,1( |(//.8/785 %(1?7,*7 :,5' 81' '$+(5 $8) (,1 u(/(.7,2160$5.(5*(1 9(5=,&+7(7 :(5'(1 .$11P f$6 fpcOh5$*0(17N :(/&+(6 '$6 v5$16*(1 75>*7N :,5' 817(5 x(5:(1'81* (,1(6 +2&+$89?6(1'(1 o,.526.236 ',5(.7 0,7 j,/)( )(,1 $86*(=2*(1(5 i/$6.$3,//$5(1 ,1 '(1 x25.(51 %()58&+7(7(5 g,=(//(1 ,1-,=,(57 Jc%%P VPVT %KP YW@ '(5 g0%511/,&+(1 v,(5(1P p$&+ (,1(5 v5$*=(,7 921 (7:$ TR v$*(1 :(5'(1 ',( p$&+.200(1 *(%25(1P g7:$ TRAUR@ '(5 p$&+.200(1 75$*(1 '$6 v5$16*(1 ,1 ,+5(0 i(120P l('(6 v5$16*(1O326,7,9( v,(5 ',(6(5 i(1(5$7,21 5(35>6(17,(57 0,1'(67(16 (,1 81O $%+>1*,*(6 k17(*5$7,216(5(,*1,6N 'P +P '$6 v5$16*(1 ,17(*5,(57 =8)>//,* 81' 81*(5,&+O 7(7 $8) (,1(0 e+5202620P f$+(5 6,1' ',( v,(5( *(1(7,6&+ 1,&+7 ,'(17,6&+P l('(6 ,67 9,(/0(+5 '(5 d(*5@1'(5 J)281'(5K (,1(6 1(8(1 o$8667$00(6P o$1&+0$/ .2007 (6 925N '$M (,1 v(,/ '(5 v5$16*(1.23,(1 ,1 (,1(1 =:(,7(1 i(1/2&86 ,16(5,(57 81' '$+(5 %(,0 1>&+67(1 m5(8=81*66&+5,77 81$%+>1*,* 9(5(5%7 :,5' Ju(*5(*$7,21KP u2 (1767(+(1 '$11 $86*(+(1' 921 (,1(0 75$16*(1(1 h281'(5 =:(, 75$16*(1( u8%/,1,(1P

Transgenkonstrukt

Promotor

pA

mRNA

A (n)

(a) Herstellung transgener Mäuse Injektion von DNA in den Vorkern befruchteter Oozyten Zygote

Übertragung injizierter Oozyten in scheinschwangere Empfängertiere

^ ]

Züchtung transgener „founder”

^ transgener „founder”

Injektionskapillare mit DNA Zona pellucida

Pronuklei

50 % der Nachkommen tragen das Transgen

(b)

c%%P VPVT v5$16*(1( o>86(P J$K u&+(0$7,6&+( f$567(//81* (,1(6 786( 0,77(/6 x25.(51,1-(.7,21 %()58&+7(7(5 g,=(//(1P f,( fpc :,5' ,1 (,1(1 '(5 %(,'(1 r5218./(, ,1-,=,(57P f,( ,1-,=,(57(1 |86(N ',( '$6 v5$16*(1 75$*(1N :(5'(1 (7:$ TAV 0$/ 62 *52M :,( k+5( i(6&+:,67(5 2+1( v5$16*(1P g,1(1 :(,7(5(1 u&+8% (5+,(/7 ',(6( h256&+81*65,&+781* $/6 o,77( '(5 $&+7=,*(5 l$+5( ',( t(/(9$1= '(5 g5*(%1,66( 921 ,1 9,752 c1$/=,6,21 817(568&+7 :(5'(1P f,( *(1(7,6&+( x(5>1'(581* (,1(6 1$7@5/,&+ J63217$1K (1767$1'(1(1 087$17(1 o$8667$00(6 '(5 +3* o$86 Jj86(1 ,67 ',( 32671$7$/( g17:,&./81* '(5 i21$'(1 %/2&.,(57N :$6 ',( w1)58&+7%$5.(,7 '(5 o87$17(1 +(592558)7P f,( g,1.5(8=81* '(6 i1tj y,/'7O 12711/,&+(1 81' :(,%/,&+(1 v,(5(1P

SMXMR j./#+L/54 5.$ +./#+L). l;53% f,( g5=(8*81* 921 o87$17(1 0,7 (,1(5 =,(/*(5,&+7(7(1 *(1(7,6&+(1 x(5>1'(581* ,1 (,1(0 %(67,007(1 i(1/2&86 %$6,(57 $8) '(5(1 g,1)@+581* '85&+ +202/2*( t(.20O %,1$7,21 ,1 (0%586(1 ,67 ',( o?*/,&+.(,7 '(5 +2O 02/2*(1 t(.20%,1$7,21 '(5 *(120,6&+(1 u(48(1=(1 0,7 (;2*(1(5 fpc 817(5 *(O (,*1(7(1 d(',1*81*(1P o,77(/6 g/(.75275$16)(.7,21 *(/$1* S[ZY ',( (567( *(=,(/7( g,1)@+581* (,1(5 o87$7,21 '85&+ +202/2*( t(.20%,1$7,21 ,1 guO|(//(1 ,1 9,752P

TVT

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

f,( (567( *(=,(/7 ,1 '(5 m(,0%$+1 087,(57( o$86 817(5 '(5 x(5:(1'81* +202/2* 5(.20%,1,(57(5 guO|(//(1 :85'( S[Z[ %(6&+5,(%(1P f(5 (567( u&+5,77 %(, ',(6(5 v(&+1,. ,67 ',( g/(.75275$16)(.7,21 Jg/(.752325$7,21K (;2*(1(5 fpc ,1 guO|(//(1P f,( (;2*(1( fpc (17+>/7 ',( %($%6,&+7,*7( o87$7,21 81' -(:(,/6 %(1$&+%$57( +202/2*( J*(120,6&+(K u(48(1=(1 =80 5(/(9$17(1 i(1O /2&86 J7$5*(7,1* x(.725K Jc%%P VPVUKP f85&+ '(1 r52=(66 '(5 +202/2*(1 t(.20%,O 1$7,21 :,5' ',( 087,(57( (;2*(1( u(48(1= $1 '(5 %($%6,&+7,*7(1 u7(//( ,0 i(1/2&86 *(*(1 ',( *(120,6&+( u(48(1= $86*(7$86&+7P f,( h>+,*.(,7 =85 +202/2*(1 t(.20O %,1$7,21 ,67 +,(5%(, (,1( 1$7@5/,&+( g,*(16&+$)7 $8&+ 921 guO|(//(1N ',( '85&+ g1O =/7 '85&+ (,1 u(/(.7,2160$5.(5*(1 (56(7=7 J5(3/$&(0(17 76(17,(5(1 +202/2*( u(48(1=(1 ,0 x(.725N y,/'7//,*(5 J1,&+7O+202/2*(5K t(.20%,1$7,21 /,(*7 %(, '(1 0(,67(1 g;3(5,O 0(17(1 ,0 d(5(,&+ 921 S\U %,6 S\WRR 5(6,67(17(5 m/21(P j$7 0$1 (,1(1 +202/2* 5(.20%,1,(57(1 guO|(//./21 ,'(17,7=,(57N :(5'(1 ',(6( |(//(1 ,1 m8/785 9(50(+57 81' ,1 g0%5+/7 0$1 '$6 u7$',80 '(5 d/$672=5(1 p$&+.200(1N '(5(1 i(:(%( 9,(/( |(//(1 0,7 '(0 75$16*(1(1 guO|(//Oi(12700(1N ',( 6,&+ ,1 ,+5(5 h(//)$5%( 817(56&+(,'(1P f,( p$&+.200(1N ',( (,1(1 *52M(1 c17(,/ 921 |(//(1 '(6 guO|(//Oi(1271'(57(1 guO|(//(1 ,1 d/$672=86(N '(5(1 i(:(%( 6,&+ $86 |(//(1 '(5 d/$672=1'(57(1 guO|(//(1 =86$00(16(7=7N :(5'(1 *(%25(1P

c8635>*81* '(6 e+,0>5,6086 0(+5 2'(5 :(1,*(5 67$5. *(9(&.7(6 2'(5 *(675(,)7(6 h(//P p81 6&+/,(M7 0$1 921 '(5 d(7(,/,*81* '(5 guO|(//(1 $0 c8)%$8 921 j$87 81' h(// $8) '(5(1 d(7(,/,*81* $0 m(,0%$+1*(:(%(P m5(8=7 0$1 &+,0>5( 0>11/,&+( v,(5( 0,7 y,/'7127127+,* Jn(7$/087$17(KP c8&+ .?11(1 (5=(8*7( o87$7,21(1 3+>1271*(1N ,1 :(/&+(0 o$8667$00 6,( (5=(8*7 :85'(1P k1 ',(6(1 h>//(1 )@+5(1 ',(6(/%(1 o87$7,21(1 =8 817(56&+,('/,&+(1 r+>O 127//( '(87(1 $8) ',( g;,67(1= 921 67$00$%+>1*,* 817(56&+,('/,&+ $86*(35>*7(1 h$.725(1 +,1N ',( (,1( c86:,5.81* $8) ',( 3+>127*81* '(6 817(568&+7(1 i(16 +$%(1 .?11(1 JNN675$,1O63(&,7& 02',7(56DDKP

SMXMRMP a%)30)%,Y s)%2-/$%,,% &=2 b934)3#(% e)"2/3% f,( e87*67(1 /(7$/(1 +(5(',7>5(1 m5$1.+(,7(1 ,1 f(876&+/$1'P f$6 %(7525(1( i(1 :85'( S[Z[ ./21,(57P d(, '(0 i(1352'8.7 +$1'(/7 (6 6,&+ 80 (,1(1 e+/25,'Ok21(1.$1$/N '(1 NN&+1/,&+(5 ,67P d(621'(56 ',( ,17(67,1$/(1 x(56723)81*(1 6,1' *(*(1@%(5 '(1 p8//087$17(1 '(87O /,&+ 9(50,1'(57 81' ',( %(5/(%(165$7( (5+?+7P f$'85&+ 67(//(1 6,( (;=(//(17( o2O '(//( '$5N %(, '(1(1 ',( eh r$7+2*(1(6( '(5 n81*(1 817(568&+7 :(5'(1 .$11P

TVX

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

SMXMRMQ s)%2-/$%,,% &=(2%. :52 h$%.4)&):)%25.' -%.3#(,)#(%2 f%.$%&%+4% f,( ,1=:,6&+(1 :(,79(5%5(,7(7( p87=81* '(5 .12&.O287 v(&+1,. ,1 '(5 i581'/$*(1O )256&+81* +$7 =8 (,1(0 )@5 ',( o(',=,1 :,&+7,*(1 |86$7=$63(.7 *()@+57\ |8:(,/(1 (1767(+(1 0(+5 2'(5 :(1,*(5 =8)>//,* v,(5087$17(1N '(5(1 r+>1271277 '(5 o87$17( 80O *$1*(1 :(5'(1P u3>7(5( h81.7,21(1 (,1(6 |,(/*(16 ,1 $1'(5(1 i(:(%(1 .?11(1 620,7 $1$///(1 6(+5 1@7=/,&+N ,1 '(1(1 ',( g17:,&./81* =:(,(5 u758.785(1 (1* 0,7(,1$1'(5 *(.233(/7 ,67N :,( =P dP ',( g17:,&./81* 921 o86.(/1 81' ,+5( k11(59,(581* '85&+ o27251(8521(P q+1( o86.(/1 9(5.@00(51 ',( p(59(1N 81' 2+1( k11(59,(581* '(*(1(5,(5(1 ',( o86.(/1P k67 181 (,1 i(1352'8.7 )@5 ',( g17:,&./81* %(,'(5 u758.785(1 (66(17,(//N .$11 ',( i(1)81.7,21 ,1 (,1(5 u758.785 $86*(6&+$/7(7 :(5'(1 J=P dP o27251(8521(K 81' ,+5( c86:,5.81*(1 $8) ',( $1'(5( u758.785 Jo86.(/K 817(568&+7 :(5'(1P

TVZ

V o2/(.8/$50(',=,1,6&+( o(7+2'(1 Cre Maus

cre

X

gefloxte Maus

cre Ziel-Gen

cre

cre

Ziel-Gen

Ziel-Gen

Ziel-Gen

Induktion während der Ontognese gemäss den regulatorischen Elementen von Cre oder extern durch einen Indikator

cre

cre

Ziel-Gen

Ziel-Gen deletiert

c%%P VPVY |8&+76&+(0$ )@5 ',( .21',7,21$/( o87$*(1(6( ,1 o>86(1 '85&+ +202/2*( 81' NN6,7(O63(&,7&DD t(.20%,1$7,21P p85 (,1 c//(/ '(6 |,(/*(16 ,67 '$5*(67(//7P |:(, 81$%+>1*,*( o$8667>00( 6,1' +,(5)@5 1?7,*P g,1 u7$00 (;35,0,(57 ',( e5(Ot(.20%,1$6( ,1'8=,(5%$5 2'(5 ,1 *(:(%(63(=,76&+(5 h250P |(//(1 ',( e5( 1,&+7 (;35,0,(5(1 6,1' 0,7 6&+:$5=(0 t$1' '$5*(67(//7N ',(-(1,*(1N ',( (;35,0,(5(1 0,7 %/$8(0 t$1'P f(5 $1'(5( o$8667$00 75>*7 '(1 NN*(92;7(1DD n2&86 '(6 |,(/*(16N :(/&+(6 ,1 $//(1 |(//(1 (;35,0,(57 :,5'P p$&+ m5(8=81* (17O +>/7 -('( |(//( '$6 e5(Oi(1 81' '$6 NN*(92;7(DD i(1P |8 (,1(0 %(67,007(1 |(,7381.7 '(5 g17:,&./81* :,5' e5( *(:(%(63(=,76&+ (;35,0,(57 J%/$8 805$1'(7( |(//(K 2'(5 1$&+ |8*$%( (,1(6 k1'8.7256 921 $8M(1 $.7,9,(57 J1,&+7 *(=(,*7KP k1 '(1 5(/(9$17(1 i(:(%(1 71'(7 t(O .20%,1$7,21 67$77N ',( =85 g,1)@+581* '(5 %($%6,&+7,*7(1 o87$7,21 )@+57 J%/$8 805$1'(7( |(//( 0,7 +(//%/$8(0 j,17(5*581'KP

SMXMSMP f%7%"%30%:)&)3#(% l54!'%.%3% f,( 62*(1$117( NN92;O$1'O'(/(7(DD u75$7(*,( Jc%%P VPVXK :85'( =8(567 )@5 ',( ,1 9,92 c1$/86(N ',( =:(, 62/&+( c//(/( 75$*(1N =(,*(1 .(,1(5/(, 3$7+2/2*,6&+(1 r+>1277=/,&+( x(5(5%81*602', .?11(1 817(56&+,('(1 :(5'(1 Jc%%P WPSKP d(,0 '20,1$17(1 g5%*$1* (5.5$1.(1 67$7,67,6&+ *(6(+(1 WR@ '(5 p$&+O .200(1 '(6 (5.5$1.7(1 o(5.0$/675>*(56P f,(6 .$11 '$5$1 /,(*(1N '$M JSK ',( c.O

autosomal rezessiv

autosomal dominant

X-chromosomal rezessiv

c%%P WPS u7$00%>80( o(1'(/6&+(5 x(5(5%81*60867(5P x2//67>1',* *()@//7( u127//,*(1 r(5621(1P j$/% *()@//7( u127//,*(1 r(5621(1N ',( *(127127//,* 6(,1P d(,0 $872620$/ '20,1$17(1 g5%*$1* 6,1' %(, (,1(0 3+>1275( g5.5$1.81*(1

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physiologische liganden-abhängige Aktivierung

Mutationen der extrazellulären Domäne

Mutationen des Transmembransegmentes

Mutationen der TyrosinKinasedomäne

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Expansionswahrscheinlichkeit

pathologische Funktion

Poly (A)

minimal

–

Poly (A)

hoch

+ (späte Manifestation und langsame Progredienz)

Poly (A)

hoch

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(CAG)10-35

CAP

5´– UTR

kodierende Sequenz (CAG)\40

CAP

kodierende Sequenz (CAG)\100

CAP

kodierende Sequenz

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PLZF-RAR· Fusion

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Transkription aktiviert

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XPX u7?581*(1

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393

Mutationen N

C Transaktivierung

DNA-Bindung

Regulator-Domäne

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X q1.2/2*,6&+( m5$1.+(,7(1

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XPZ h$0,/,>5( v8025(5.5$1.81*(1

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UUY

RET

GDNF

CD

CRD GDNF-R·

620 FMTC 634 MEN-2A

Zellmembran TK1 TK 2

918 MEN-2B

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UVR

X q1.2/2*,6&+( m5$1.+(,7(1 Desmoide CHRPE 1061

1309 1450

typische Polyposis attenuierte FAP

N

1

500

1000

1500

2000

2500

C 2843 AA

APC

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UWT

X q1.2/2*,6&+( m5$1.+(,7(1 1012 10 11 10 --2

10 10 CR

10 9 10 8 107 10 6

M R D

Morphologie Southern Blot

immunologische 10 --4 Marker Kombinationen 10 --6 PCR

10 5 10 4 103 10 2 10 1 10 0

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SRX p250$/=(//(1 Jm$3P VPUPTKP c%%P XPTW =(,*7 ,1 (,1(0 u&+(0$ m,1(7,.(1 921 n(8O .>0,(=(//(1 :>+5(1' (,1(5 e+(027+(5$3,( 81' '$1$&+P d(, 1$+(=8 $//(1 m,1'(51 0,7 cnn *(/,1*7 6&+21 :>+5(1' '(5 (567(1 9,(5 y2&+(1 '(5 t(0,66,216,1'8.7,21 (,1 c%6(1.(1 '(5 n(8.>0,(=(//(1=$+/ 817(5 ',( p$&+:(,6*5(1=( .219(17,21(//(5 v(&+1,.(1P f$6 SRPRRRO)$&+ (5+?+7( c89?681*69(50?*(1 '(5 retOx(5)$+5(1 *(O 67$77(7N ,1',9,'8(//( w17(56&+,('( ,1 '(5 g/,0,1,(581* 0$/,*1(5 |(//(1 (%(162 =8 (5)$66(1 :,( '(1 p$&+:(,6 5(=,',9,(5(1'(5 n(8.>0,(1 o21$7( 925 (,1(5 ./,1,6&+(1 o$1,)(67$7,21P h@5 ',( retOf,$*1267,. .200(1 %(, n(8.>0,(1 925 $//(0 =:(, m$7(*25,(1 921 |,(/6(48(1=(1 ,1 h5$*(\ ',( 02/(.8/$5(1 }48,9$/(17( &+5202620$/(5 c%(55$7,21(1 81' ',( 620$7,6&+(1 t(.20%,1$7,21(1 921 k*O 81' vetOi(1(1P y,( ,0 m$3P UPW '$5*(67(//7N :(5'(1 ',( 9$5,$%/(1 t(*,21(1 '(5 k*O 81' vetOm(77(1 $86 9(56&+,(O '(1(1 fpcOg/(0(17(1 =86$00(1*(6(7=7 81' ,1',9,'8(// 02',7=,(57N 62 '$M '(1 x(5.1@3)81*667(//(1 (,1 ./2163(=,76&+(5 e+$5$.7(5 =8.2007P f,(6( ./2163(=,7O 6&+(1 u(48(1=(1 .?11(1 %(67,007 81' $/6 ,1',9,'8(//( i(1621'(1 =85 %(535@)81* '(6 t(0,66,21667$786 +(5$1*(=2*(1 :(5'(1P d(, (7:$ [W@ $//(5 r$7,(17(1 0,7 p(2O 3/$6,(1 '(6 ///(1 3(56,67,(5(1 n(8.>0,(O

XPSR p$&+:(,6 6(+5 ./(,1(5 o(1*(1 0$/,*1(5 |(//(1

UWU

1 klinische Manifestation

10 –1 10 –2

CR

10 –3

M R D

10 –4 10 –5 10 –6 10 –7 10 –8

Heilung 0 RI KR

1

2 E

3

4 Jahre

Therapie

c%%P XPTW u&+(0$7,6&+( f$567(//81* 817(56&+,('/,&+(5 m,1(7,.(1 921 0$/,*1(1 |(//(1 %(, cnn r$7,(17(1 :>+5(1' (,1(5 e+(027+(5$3,( 81' 1$&+ c%6&+/8M '(5 d(+$1'/81*P v+(5$O 3,(3+$6(1\ t(0,66,216,1'8.7,21 JtkKN m2162/,',(581*Bt(,17(16,9,(581* JmtKN g5+$/781* JgKP r$7,(17(1 ,1 62*(1$117(5 .203/(77(5 t(0,66,21 JetK .?11(1 $8) retOp,9($8 12&+ j,1:(,6( )@5 0,1,0$/( n(8.>0,(=(//3238/$7,21(1 JotfK =(,*(1P

=(//(1 12&+ 0(+5(5( o21$7( %,6 6,( '$11 *$1= 9(56&+:,1'(1P u&+/,(M/,&+ (;,67,(57 (,1( j2&+5,6,.2*5833( 921 (7:$ SW@ '(5 m,1'(5 0,7 cnnN %(, '(1(1 ',( n(8.>0,(O =(//(1=$+/ 185 .1$33 817(5 ',( p$&+:(,6*5(1=( 921 u7$1'$5'9(5)$+5(1 $%*(6(1.7 :,5' 81' $8) +2+(0 p,9($8 3(56,67,(57 2'(5 @%(5 0(+5(5( o21$7( (,1(1 67(7,*(1 y,('(5$167,(* =(,*7] ,1 ',(6(1 h>//(1 .2007 (6 )$67 ,00(5 =80 ./,1,6&+(1 t(=,',9P f,(6( 1(8(1 g5.(1171,66( :(5'(1 '(5=(,7 )@5 '(1 g17:85) ,1',9,'8$/,6,(57(5 v+(5$O 3,(.21=(37( 187=%$5 *(0$&+7P g,1 :(,7(5(6 o$5.(5687*( t(.20%,1$7,21(1N :(/&+( %(, (7:$ VR@ '(5 r$7,(17(1 0,7 cnnN UR@ 0,7 con 81' [W@ 0,7 eon 1$&+:(,6%$5 6,1'P f$ 6,&+ ',(6(6 o$5.(561'/,&+N '$M 6,&+ +,(5 ',( f$7(1 =80 t(0,66,21667$786 $8) retOp,9($8 -( 1$&+ m5$1.+(,76%,/' '(87/,&+ 817(56&+(,'(1P d(, r$7,(17(1 0,7 r+O326,7,9(5 cnn 71'(1 6,&+ 6(/%67 1$&+ g55(,&+(1 (,1(5 .203/(77(1 +>0$72/2*,O 6&+(1 t(0,66,21 (17635(&+(1' '(5 6(+5 +2+(1 t(=,',95$7( 0(,67 12&+ n(8.>0,(O =(//(1N :>+5(1' ',( ,17(16,9,(57(1 v+(5$3,(675$7(*,(1 %(, r$7,(17(1 0,7 $)VO$//S t(O .20%,1$7,21 j(,/81*(1 (5=,(/(1 .?11(1N ',( '$11 0,7 (,1(0 1(*$7,9(1 retOd()81' (,1+(5*(+(1P c8&+ %(, '(5 con =(,&+1(7 6,&+ (,1 ',5(5(1=,(57(6 d,/' $%P u2 .2007

Verknüpfungsregion

J‰1

Sonde

CTTGGGG · TG T T T T C AGGCCTTCCGGTGGGGGATA AAC T T GGG · ATAAC NNNNNNN PPP D‰2 NN NNNNNNNN J‰1 V‰1 D‰3

Sonde

3

2

1

10-1 10-2 10-3 10-4 10-5 10-6

Sonde: GTGTTTTCAGGCCTTCC

Sonde: CTACAGGAAGGTGGGTACTG

Sonde: ACTAGGACAACTTCCTACACTGG

D

C

Monate 1 3 6

681'(1 r52%$1'(1 JeK %(67,007 :,5'P k1 ',(6(0 h$// /,(*7 ',( g03O 71'/,&+.(,7 '(5 '5(, u21'(1 %(, -(:(,/6 (,1(5 n(8.>0,(=(//( 817(5 SRR RRR 1250$/(1 n0,(=(//(1 0(+5 1$&+:(,6(1 /$66(1N 71'(7 6,&+ %(, r$7,(17 U =8 $//(1 w17(568&+81*6O =(,7381.7(1 12&+ (,1( %(75>&+7/,&+( o(1*( 5(6,'8$/(5 d/$67(1] %(, ',(6(0 r$7,(17(1 .$0 (6 =:(, o21$7( 63>7(5 =8 (,1(0 ./,1,6&+(1 t(=,',9P

CTTG · T GCC T C T TCCTTCCTAC AGGAAGG T GGGTACTGGGGGGT · ACACCGATAAC NNNNNNNNNNPP V‰1 NNNNNNNN D‰2 D‰3 PP J51

Sonde

CTTGGGGAACT · AGG AC AACTTCCTACACTGGGGG · ACACCGATAAAC PP NNNNN D‰2 V‰1 D‰3 J‰1

V‰1

3´

c%%P XPTX retOc1$/0,(=(//(1 n(8.>0,(

q1.2*(1(

e+5202620$/( c%(55$7,21

j>87*.(,7 J,16*(6$07 %(, cnnBconK

cnn

%&5O$%/

7J[]TTK

7(/O$0/S

7JST]TSK

3%;SO(T$ $)VO$//S

7JS]S[K 7JV]SSK

6,/O7$/S

'(/JS3UTK

g5:$&+6(1( VR @ m,1'(5 W@ g5:$&+6(1( U @ m,1'(5 TW @ TW @ r5>Od UR @ r5>Or5>Od u>8*/,1*( YR @ SR ATR @ vOcnn

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XPST v(/20(5$6($.7,9,7>7

UWY

v$%P XP[ c1*,2*(1(7,6&+( 81' $17,$1*,2*(1(7,6&+( h$.725(1 c1*,2*(1(6()$.725(1

c17,Oc1*,2*(1(6()$.725(1

c1*,2*(1,1 c1*,232(7,1 g3,'(50$/ *52:7+ )$&725 JgihKsBt h,%52%/$67 *52:7+ )$&725 JhihKsBt j(3$72&O 0$7232(6( '@5)(1 ,1 ,+5(0 d(67$1' $%(5 1,&+7 925=(,7,* *()>+5'(7 :(5'(1P k1 ',(6(1 |(//3238/$7,21(1 :,5.7 '$6 g1=7=/,&+( vvciiiOo27,9( $1.233(/7N 62 '$M ',( 1$&+)2/*(1'(1 fpcO x(5/867( ,0 v2&+7(5675$1* 1,&+7 ',( r5,0>5%(67$1'7(,/( '(5 e+5202620(1(1'(1 (5O )$66(1 Jm$3P UPXPSKP u20$7,6&+( |(//(1 %(6,7=(1 ,0 i(*(16$7= =8 m(,0=(//(1 1250$O /(5:(,6( .(,1( v(/20(5$6($.7,9,7>7] ,+5( v(,/81*6.$3$=,7>7 ,67 '(01$&+ %(*5(1=7P g,1( *(:,66( g;35(66,21N ',( '(1 c/7(581*6352=(M 352/21*,(57N 71'(7 6,&+ $%(5 ,1 63(=,76&+(1 |(//3238/$7,21(1 0,7 u7$00=(//&+$5$.7(5 :,( (7:$ +>0$7232(7,6&+(1 x25/>8)(5=(//(1N d$6$/=(//(1 '(5 g3,'(50,6 2'(5 |(//(1 '(5 352/,)(5$7,9(1 |21( ,1 ,17(67,1$/(1 m57 %(2%$&+7(7] ',(6 :(,67 $8) (,1(1 v(/20(5$6(O81$%+>1*,*(1 o(&+$1,6086 '(5 v(/20(59(5/>1*(581* +,1P f,(6( g5.(1171,66( .?117(1 @%(5 ',( g17:,&./81* 921 v(/20(5$6(Ok1+,%,725(1 $8&+ 7+(5$3(87,6&+( k03/,.$7,21(1 +$%(1P f,( 61*( '(6 v(/20(5%(5(,&+(6P k1 '(1 0(,67(1 v8025=(//(1 .2007 (6 @%(5 (,1( 3$7+2/2*,6&+( c.7,9,(581* '(5 v(/20(5$6( =85 v(/20(59(5/>1*(581*P

d(2%$&+781*(1 $1 o>86(1 ,17(5(66$17N '(5(1 .$7$/86( 6,1' =81>&+67 /(%(16)>+,* 81' )(57,/P c8&+ v8025( .?11(1 (1767(+(1] ',(6 =(,*7N '$M ',( v(/20(O 5$6($.7,9,7>7 .(,1( &21',7,2 6,1( 48$ 121 '(5 m5(%6(17:,&./81* '$567(//7P g567 63>7(5( p$&+.200(1 JXP i(1(5$7,21K ',(6(5 o>86( =(,*(1 '$11 f()(.7( ,1 '(5 u3(50$72O *(1(6( 62:,( j>0$7232(6( 81' (17:,&.(/1 =81(+0(1' e+5202620(1$120$/,(1N 62 '$M 6,&+ '(5 ,00(5 67>5.(5( v(/20(59(5/867 ,1 :(,7(5(1 i(1(5$7,21(1 $/6 n(7$/O )$.725 (5:(,6(1 '@5)7(P f(112&+ /$66(1 6,&+ ',(6( f$7(1 1,&+7 810,77(/%$5 $8) '(1 o(16&+(1 @%(575$*(1P u2 %(6,7=(1 o>86( (7:$ =(+10$/ />1*(5( v(/20(5( $/6 o(1O 6&+(1N ,+5( 3+7 %,6 =80 c8)75(7(1 921 h81.7,2169(5/8O 67(1 ,67 $/62 *5?M(5P c8&+ .?117( ',( 6(+5 9,(/ />1*(5( n(%(16=(,7 '(6 o(16&+(1 0,7 ./,1,6&+(1 o$1,)(67$7,21(1 9(5%81'(1 6(,1N ',( %(, o>86(1 1,&+7 %(2%$&+7(7 :(5'(1P g6 .2007 +,1=8N '$M '(5 c86)$// '(5 v(/20(5$6( ,1 '(1 .12&.O287Oo>86(1 '85&+ 12&+ 81=85(,&+(1' &+$5$.7(5,6,(57(N $/7(51$7,9( u&+87=0(&+$1,60(1 *(*(1 v(/20(59(5.@5=81*(1 .203(16,(57 :(5'(1 .?117(P c1'(5(56(,76 :>5( (6 92567(//%$5N '$M '(5 g,16$7= 921 v(/20(5$6(Ok1+,%,725(1 (,1 %5(,7(5(6 p(%(1:,5.81*663(.7580 =(,*7 $/6 ',( *(=,(/7( c866&+$/781* '(6 g1=6(17,(5(1 (,1(6 '(5 %(,'(1 k1,7,$7,216.2'216N wciN wic 81' wcc ',( 0?*/,&+(1 v5$16/$7,2166723.2'216P

TP r52.$5+O 5(1' o87$7,21(1 ,1 u758.785*(1(1 .$80 32/$5( g5(.7( =(,*(1P UP tpcOu3/(,M352=(66( :(5'(1 %(, d$.7(5,(1 1,&+7 %(2%$&+7(7P

VMPMPMR o,!3-)$%K h.3%24)/.3%,%-%.4% 5.$ s2!.30/3/.3 r/$60,'( 6,1' =,5.8/>5(N 6,&+ $872120 9(50(+5(1'(N (;75$&+5202620$/(N '233(/O 675>1*,*( fpcOo2/(.@/(N '(5(1 i5?M( 81' c1=$+/ 6(+5 817(56&+,('/,&+ 6(,1 .$11 JS4SRK %,6 T4SRN d$6(13$$5(N T %,6 SRR m23,(1 352 d$.7(5,(1=(//(KP f,( *5?M(5(1 r/$60,'( 75$*(1 i(1(N ',( ,+5( %(575$*81* $8) $1'(5( d$.7(5,(1 (50?*/,&+(1P g,1 :(,7(5(6 e+$5$.7(5,67,.80 ,67 '$6 y,57663(.7580\ o$1&+( r/$60,'( .?11(1 185 =:,6&+(1 d$.7(5,(1 '(56(/%(1 2'(5 (,1(5 1$+( 9(5:$1'7(1 c57 @%(575$*(1 :(5'(1N $1'(5( .?11(1 =:,6&+(1 62 817(56&+,('/,&+(1 c57(1 :,( u7$3+1*,* 921 '(5 '(5 &+5202620$/(1 fpc] %(, '(5 |(//7(,/81* :(5'(1 ',( 925O +$1'(1(1 r/$60,'( 0(+5 2'(5 :(1,*(5 =8)>//,* $8) ',( v2&+7(5=(//(1 9(57(,/7P g,1( :(,7(5( i5833( 921 %(:(*/,&+(1 *(1(7,6&+(1 g/(0(17(1 :,5' $/6 k16(57,216O (/(0(17( %=:P v5$16326216 %(=(,&+1(7 Jc%%P YPUKP k16(57,216(/(0(17( 6,1' 02%,/( *(1(7,6&+( g/(0(17(N ',( ,+5(1 r/$7= ,0 i(120 >1'(51 .?11(1P k0 t$+0(1 '(5 v5$16326,7,21 :,5' (17:('(5 (,1( m23,( '(6 k16(57,216(/(0(17(6 $1 (,1(5 1(8(1 u7(//( ,1 ',( &+5202620$/( 2'(5 r/$60,'Ofpc ,16(5,(57N :2%(, '$6 85635@1*/,&+( k16(5O 7,216(/(0(17 $1 6(,1(0 r/$7= %/(,%7N 2'(5 '$6 k16(57,216(/(0(17 6(/%67 :(&+6(/7 '(1 r/$7= 81' +,17(5/>M7 (,1( f(/(7,21 $1 '(5 $/7(1 u7(//(P k16(57,216(/(0(17( :(5'(1 $1 '(1 g1'(1 +>87* '85&+ ,'(17,6&+(N ,1 '(5 u(48(1= *(*(1/>87*( p8./(27,')2/*(1 %(*5(1=7N ',( 62*(1$117(1 NN,19(57(' 5(3($76DDP f,(6( 5$+0(1 u(48(1=(1 (,1N ',( )@5 r527(,1( .2',(5(1N ',( )@5 '(1 r52=(M '(5 v5$16326,7,21 (5)25'(5/,&+ 6,1' Jv5$16O 326$6(N t(62/9$6(KP d(, '(5 v5$16326,7,21 +$1'(/7 (6 6,&+ 80 (,1( 1,&+7O+202/2*( t(.20%,1$7,21N 62 '$M ,'(17,6&+( k16(57,216(/(0(17( $1 9?//,* 817(56&+,('/,&+(1 u7(//(1 '(6 %$.7(5,(//(1 i(1206 ,17(*5,(5(1 .?11(1P v5$16326216 6,1' 35,1=,3,(// */(,&+$57,* $8)*(%$87 :,( k16(57,216(/(0(17(] =86>7=/,&+ =8 '(1 i(1(1 )@5 v5$16O 326,7,216)81.7,21(1 75$*(1 v5$16326216 -('2&+ 12&+ $1'(5( i(1(N %(,63,(/6:(,6(

IR

Pathogenitätsgen (Antibiotikaresistenz, Virulenzfaktor)

Mobilisationsgene (Resolvase, Transposase)

IR

ATTAT TAATA versetzter Schnitt im Wirtschromosom

TAATA

ATTAT

Transposon IR

IR

IR

IR

ATTAT TAATA IR

IR

TAATA

ATTAT

ATTAT TAATA

c%%P YPU u&+(0$7,6&+(5 c8)%$8 (,1(6 v5$16326216 81' o2'(// )@5 ',( k16(57,21 (,1(6 v5$16O 326216P i(:?+1/,&+ 6,1' ',( '$6 v5$1632621 9$1.,(5(1(1 u(48(1=(1 ,1 '(0 y,576&+5202620 ,'(17,6&+P ktN ,19(57(' 5(3($7P

YPS o2/(.8/$5( d$.7(5,2/2*,(

UXU

c17,%,27,.$5(6,67(1=(1 2'(5 x,58/(1=)$.725(1P g7:$ (,10$/ 817(5 SRK A SRP |(//(1 (,1(5 i(1(5$7,21 :,5' '$6 g/(0(17 $1 (,1( $1'(5(N 1$+(=8 %(/,(%,*( u7(//( '(6 i(O 1206 @%(575$*(1P r/$60,'( 2'(5 v5$16326216 6,1' )@5 '$6 %(5/(%(1 '(5 d$.7(5,(1=(//( 1,&+7 81O %(',1*7 (5)25'(5/,&+N 9(5/(,+(1 ,+5 -('2&+ g,*(16&+$)7(1N ',( 817(5 %(67,007(1 d(O ',1*81*(1 (,1(1 u(/(.7,2169257(,/ '$567(//(1N =P dP ',( h>+,*.(,7N 81*(:?+1/,&+( &+(O 0,6&+( x(5%,1'81*(1 $/6 p$+581*648(//( =8 9(5:(1'(1N v2;,1( 2'(5 x,58/(1=)$.O 725(1 =8 67 %(58+7 ',( d('(8781* '(5 v5$16326216 $8) =:(, h$.725(1\ SP ,0 x(5*/(,&+ =8 r/$60,'(1 =(,*(1 v5$16326216 (,1 (5:(,7(57(6 y,57663(.7580 81' TP '(5 c..808/$7,21 0(+5(5(5 t(6,67(1=O 2'(5 x,58/(1=*(1( $1 (,1(0 *(1(7,6&+(1 n2&86P v$%P YPT o(',=,1,6&+ %('(876$0( g,*(16&+$)7(1N ',( '85&+ r/$60,'( 81' v5$16326216 @%(5O 75$*(1 :(5'(1 R R R

m21-8*$7,21 c17,%,27,.$5(6,67(1= r$7+2*(1,7>76O 81' x,58/(1=)$.725(1 SP c'+>6,1( 81' k19$6,1( TP v2;,1(

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UXV

Y k1)(.7,216.5$1.+(,7(1

Transformation +

freie DNA

DNA-Aufnahme

Bakterienzelle

rekombinierte Bakterienzelle nach Transformation

Transduktion

+

Aufnahme der Phagen-DNA

Bakteriophagen Bakterienzelle

Donorzelle (Plasmidhaltig)

c%%P YPV

Akzeptorzelle

Rekombination

rekombinierte Bakterienzelle nach Transduktion

Konjugation +

Rekombination

Kontakt über F+ Pili

konjugative Plasmid-Übertragung

Bakterienzelle nach Konjugation

f,( 9(56&+,('(1(1 o?*/,&+.(,7(1 '(6 i(175$16)(56 %(, d$.7(5,(1P

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YPS o2/(.8/$5( d$.7(5,2/2*,(

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VMPMPMT q%342)+4)/.3L 5.$ l/$)&)+!4)/.302/:%33% k0 |86$00(1+$1* 921 i(175$16)(5 81' t(.20%,1$7,216(5(,*1,66(1 %(, d$.7(5,(1 63,(/(1 $8&+ t(675,.7,216O 81' o2',7.$7,216352=(66( (,1( t2//(P d$.7(5,(1 6+,*.(,7N k1)(.7,216.5$1.+(,7(1 $86/?6(1 =8 .?11(1N 817(57(,/7 :(5'(1 ,1 SP 2%/,*$7 3$7+2*(1( o,.5225*$1,60(1N TP )$.8/7$7,9 3$7+2*(1( o,.5225*$1,60(1 81' UP 6$3523+5( o,.5225*$1,60(1P q%/,*$7 3$7+2*(1( o,.5225*$1,60(1 67(//(1 ,1 0(16&+/,&+(0 w17(568&+81*60$7(O 5,$/ ,00(5 (,1(1 .5$1.+$)7(1 81' '$0,7 %(+$1'/81*6:@5',*(1 d()81' '$5P p85 :(1,*( o,.5225*$1,60(1 .?11(1 =8 ',(6(5 i5833( *(5(&+1(7 :(5'(1N %(,63,(/6:(,6( o+/(1 =8 ',(6(5 i5833(] d(,63,(/( 6,1' u7$3+7 (,1(6 o,.5225*$1,6086 Jv$%P YPUKP d$.7(5,(//( r$7+2*(1,7>76)$.725(1 .?11(1 ,1 =(//67>1',*( 81' 1,&+7=(//67>1',*( o(O &+$1,60(1 817(57(,/7 :(5'(1P f,( =(//67>1',*(1 o(&+$1,60(1 ',(1(1 +>87* '(5 k1O )(.7,21 Jk19$6,21K 62:,( '(5 k17(5)(5(1= 0,7 '(1 c%:(+5925*>1*(1 '(6 y,57(6N ',( 1,&+7=(//67>1',*(1 o(&+$1,60(1 @%(51(+0(1 +>87* :,&+7,*( c8)*$%(1 %(, '(5 c86O %5(,781* ,0 i(:(%( '(6 y,57625*$1,6086P p85 (,1 9(56&+:,1'(1' *(5,1*(5 v(,/ '(5 d$.7(5,(1 ,67 $/6 m5$1.+(,76(55(*(5 $1O =86(+(1N ',( 0(,67(1 d$.7(5,(1 6,1' $/6 1$7@5/,&+(5 d(67$1'7(,/ 816(5(5 w0:(/7 1,&+7 185 9?//,* +$50/26( o,.5225*$1,60(1N 621'(51 1(+0(1 +,(5 +>87* :,&+7,*( %,2O /2*,6&+( h81.7,21(1 :$+5P f,( g17:,&./81* 816(5(6 r/$1(7(1 :>5( 2+1( d$.7(5,(1 1,&+7 0?*/,&+ *(:(6(1P f,( 0(',=,1,6&+( o,.52%,2/2*,( %(+$1'(/7 *(:,66(50$M(1 '(1 NNd(75,(%681)$//DD] '$6 6(/7(1( g5(,*1,6N '$M 6,&+ (,1 o,.5225*$1,6086 $/6 ?.2O /2*,6&+( p,6&+( '(1 0(16&+/,&+(1 y,57 *(:>+/7 +$7P f,( x2567(//81* (,1(5 '$8(5O +$)7(1 .(,0)5(,(1 w0*(%81* =85 x(50(,'81* 921 k1)(.7,216.5$1.+(,7(1 ,67 (,1( %,2/2*,6&+( h,.7,21N ',( $8) (,1(5 )$/6&+(1 y$+51(+081* '(5 y(/7 '(5 o,.5225*$O 1,60(1 %(58+7P f,( y,57Or$7+2*(1Od(=,(+81* ,67 (,1 =(175$/(5 i(6,&+76381.7 '(5 r$7+2*(1,7>76O )256&+81*P k0 n$8)( '(5 g92/87,21 +$7 6,&+ ,1 '(0 .203/(;(1 i/(,&+*(:,&+7 =:,O 6&+(1 y,57 81' r$7+2*(1 $8) -('( '(1.%$5( c%:(+55($.7,21 '(6 y,57(6 (,1( (17O 635(&+(1'( %(5/(%(16675$7(*,( (,1(6 m5$1.+(,76(55(*(56 +(5$86*(%,/'(7] '$5@%(5 +,1$86 *,%7 (6 9,(/)>/7,*( d(,63,(/(N :,( o,.5225*$1,60(1 6,&+ g,*(16&+$)7(1 '(5 y,576=(//( =8187=( 0$&+(1P f,( x,58/(1= (,1(6 o,.5225*$1,6086 ,67 (,1 9,(/6&+,&+O 7,*(5 x25*$1*N '(5 35$.7,6&+ 6>07/,&+( f(7(50,1$17(1 '(5 r$7+2*(1,7>7 %(75,57P k1 ',(6(5 +>87* 81'85&+6,&+7,*(1 m203/(;,7>7 (,1(1 NN(176&+(,'(1'(1DD r$7+2*(1,7>76O )$.725 =8 32678/,(5(1N ,67 %,6+(5 185 ,1 :(1,*(1 h>//(1 0?*/,&+ *(:(6(1 Jv$%P YPVKP k1 9,(/(1 h>//(1 08M '$921 $86*(*$1*(1 :(5'(1N '$M ',( x,58/(1= (,1(6 o,.5225O *$1,6086 $8) (,1(5 u800,(581* =$+/5(,&+(5 r$7+2*(1,7>76)$.725(1 %(58+7P v$%P YPU r$7+2*(1,7>7 921 o,.5225*$1,60(1 f(7(50,1$17(1 '(5 r$7+2*(1,7>7 R k1)(.7,21 Jc'+>5(1= 81' m2/21,6,(581* 921 u&+/(,0+$872%(59>&+(1K R k19$6,21 '(6 i(:(%(6 R c'$37$7,21 81' x(50(+581* ,0 y,57625*$1,6086 R k17(5)(5(1= 0,7 '(1 c%:(+5925*>1*(1 '(6 y,57(6 R u&+>',*81* '(6 y,57(6 o(&+$1,60(1 '(5 r$7+2*(1,7>7 R |(//67>1',*( o(&+$1,60(1 SP m$36(/ TP q%(59>&+(16758.785(1 J=P dP c'+>6,1(N c17,*(19$5,$7,21K UP c'$37$7,21 '(6 u725:(&+6(/6 R v2;,1( 81' 6(=(51,(57( h$.725(1 SP /2.$/(N $0 k1)(.7,216257 :,5.6$0( v2;,1( J=P dP m2//$*(1$6(1N j02/5(1= 81' m2/21,6,(581* v2;,1( r,/, c'+>6,1( o$75,;%,/'81*

d((,175>&+7,*81* '(5 |,/,$5%(:(*81* 5(63,5$725,6&+(5 g3,7+(/,(1 c'+>5(1= $1 u&+/(,0+$87(3,7+(/,(1 j$)781* $1 63(=,76&+(1 t(=(372575$*(1'(1 y,576=(//(1 c'+>6,21 $1 /(%/26(1 q%(59>&+(1 J=P dP m81676725K

k19$6,21 v2;,1( g1'2&87(1 u&+>',*81* '(6 80*(%(1'(1 i(:(%(6 k19$6,21 '(5 y,576=(//(

c'$37$7,21 81' x(50(+581* ,1 y,57625*$1,60(1 u,'(523+25( u725:(&+6(/ c.7,132/1*(1 '(6 y,57(6 m$36(/ c17,*(19$5,$7,21 v2;,1O9(50,77(/7 k0081*/2%8/,13527($6(1 c17,*(19(5:$1'76&+$)7

x(50(,'81* '(5 r+$*2&6,1(

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UYT

Y k1)(.7,216.5$1.+(,7(1

'(5 SXuBTUu 5tpc 0,7 63(=,(663(=,76&+(1 p8./(,16>85(6(48(1=(1 (,1(1 35,1=,3,(// 1(8$57,*(1 81' */(,&+(50$M(1 $//*(0(,1 *@/7,*(1 |8*$1* =85 k'(17,7=,(581* 921 o,.5225*$1,60(1P j,(5%(, :(5'(1 =81>&+67 0,77(/6 .216(59,(57(5 q/,*218./(27,'( (17635(&+(1'( 5tpcOi(1)5$*0(17( ,1 9,752 $03/,7=,(57N 80 $16&+/,(M(1' @%(5 (,1( u(48(1=$1$/07/,&+(5 %(.$117(5 o,.5225*$1,60(1 9(5)@*%$5 6,1'P retO*(67@7=7( SXu 5fpc u(48(1=$1$/66,*( p$&+O :(,69(5)$+5(1P o2/(.8/$5( o(7+2'(1 6,1' '257 ,1',=,(57N :2 (17635(&+(1'( m5$1.O +(,76(55(*(5 185 6&+:(5 2'(5 @%(5+$837 1,&+7 0,7 '(1 75$',7,21(//(1 %$.7(5,2/2*,O 6&+(1 w17(568&+81*69(5)$+5(1 1$&+:(,6%$5 6,1'P f,( k1',.$7,21 )@5 (,1( 02/(.8/$5( f,$*1267,. 6(, $0 d(,63,(/ '(5 v8%(5.8/26( (7:$6 $86)@+5/,&+(5 (5/>87(57P f(5 .8/785(//( p$&+:(,6 921 v8%(5.8/26(%$.7(5,(1

Kultur

Extraktion von Nukleinsäuren

Amplifikation eines 16S rRNA Genfragments

Sequenzanalyse

Computergestützte Analyse; Abgleich der Sequenz mit der Datenbank

Identifizierung

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TAT (Trans-Aktivator der Transkription)

Transkription

Spleißen

Provirus

Spleißen

NEF

Reifung

REV (Post-transkriptionaler Regulator der Genexpression) Transport Genomische GAG RNA Kernexport GAG-POL

Freisetzung

Zusammenbau ENV

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neue Prionen können mit weiteren PRPc-Molekülen interagieren

PRPc Interaktion von Prionen und PRPc

Spontane oder erblich bedingte Konversion von PRPc in PRPsc

Prionen – infektiöses PRPsc ohne Nukleinsäure

bewirkt Konversion von PRPc in infektiöses PRPsc

sporadische oder familiäre TSE

erworbene TSE neue Prionen

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Plasma-Insulinkonzentration (nmol/l)

0.50 0.40 0.30 0.20 0.10 0.00

0.0

1.5

3.0 4.5 Zeit (min)

6.0

7.5

subkutane Injektion bzw. Mahlzeit

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Plasmin ·2-Plasmininhibitor

Fibrinogen (löslich)

Fibrin (unlösliches Blutgerinnsel)

Fibrinogen-Spaltprodukte (löslich)

c%%P ZPV

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